Details of a Researcher - Suenaga, Kiyotake

Papers - Suenaga, Kiyotake

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Isolation and Total Synthesis of Ukabamide, an Antitrypanosomal Lipopeptide from a Marine Moorena sp. Cyanobacterium

Hagihara M., Kurisawa N., Iwasaki A., Taguchi R., Jeelani G., Nozaki T., Suenaga K.

Organic Letters 2025

ISSN 15237060

Human African trypanosomiasis (HAT) is one of the most lethal of the neglected tropical diseases. While the discovery of a novel antitrypanosomal drug is highly desired, the creation of a superior lead compound is challenging. Herein we report ukabamide (1), which was isolated from a marine Moorena sp. cyanobacterium, as a selective and potent antitrypanosomal lipopeptide (IC50 = 34 ± 18 nM against Trypanosoma brucei rhodesiense). Its structure was elucidated by spectroscopic analyses and degradation reactions and confirmed by total synthesis. In addition, we prepared two modified analogs and revealed the importance of the fatty acid chain length for biological activity. These findings may provide design guidelines for an antitrypanosomal drug.

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Hedopeptolide, a NO Production Inhibitor from the Marine Cyanobacterium Okeania sp.

Tojo S., Natsume N., Niino T., Iwasaki A., Suenaga K., Ohno O., Teruya T.

Journal of Natural Products 2025

ISSN 01633864

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Sealgamide: An Antitrypanosomal Lipopeptide Isolated from a Marine Okeania sp. Cyanobacterium

Wakai K., Kurisawa N., Umeda K., Jeelani G., Agusta A.L., Nozaki T., Suenaga K.

Journal of Natural Products 2025

ISSN 01633864

Sealgamide (1), a new antitrypanosomal lipopeptide, was isolated from a marine Okeania sp. cyanobacterium. Elucidation of its structure was challenging due to signal overlap caused by conspicuous rotamers but was ultimately achieved through partial hydrolysis and subsequent spectroscopic analyses. Sealgamide (1) exhibited moderate antitrypanosomal activity against Trypanosoma brucei rhodesiense (IC50 2.9 μM) while showing no antimalarial activity (IC50 > 25 μM) or cytotoxicity (IC50 > 30 μM). Furthermore, we discovered that an artificial C-terminal methyl ester analogue (2) exhibited notably enhanced antiparasitic activity.

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Toxicity of the marine glycosidic macrolides, polycavernoside E and akunolides, from Okinawan cyanobacterium Okeania sp. in mice

Yotsu-Yamashita M., Umeda K., Iwasaki A., Suenaga K.

Toxicon 250 2024.11

ISSN 00410101

The toxicity of polycavernoside E and its structurally related macrolides, akunolides A, B, and C, was evaluated in mice. These compounds were recently isolated from the marine cyanobacterium Okeania sp. collected in Okinawa, Japan. The minimal toxicity of polycavernoside E was estimated as 0.81 mg/kg by intraperitoneal injection, whereas those of akunolides A–C were >13 mg/kg. Owing to the considerable toxicity of polycavernoside E, the occurrence of this cyanobacterium should be considered in seaweed production environments.

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The Bioorganic Study of Iezoside: A Novel SERCA Inhibitor from the Marine Cyanobacterium

Kurisawa N., Iwasaki A., Suenaga K.

Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry 82 ( 11 ) 1107 - 1116 2024.11

ISSN 00379980

In this era of advanced technologies, is there still wisdom to be gleaned from nature? The answer is an unequivocal “Yes”. Discovering new natural products from nature, determining their structures, and revealing their biological activities ‐ this classical natural product chemistry is still a catalyst for innovation in a wide range of fields, including the expansion of chemical space, elucidation of life phenomena, and drug discovery. In this account, we describe a comprehensive bioorganic study of iezoside (1a), the novel marine natural product we recently discovered, including its discovery, synthesis, mode of action, and structure‐activity relationships.

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Allelopathic Activity of Leaf Wastes of Liriodendron tulipifera for Sustainable Management

Kato-Noguchi H., Hayashi K., Iwasaki A., Suenaga K.

Applied Sciences (Switzerland) 14 ( 18 ) 2024.09

Logging operations of Liriodendron tulipifera L., as timber trees, and fallen leaves in autumn from ornamental trees produce a large amount of leaf waste. In this study, the allelopathy of L. tulipifera fresh and fallen leaves was investigated for the development of potential applications of leaf waste. The extracts of fresh and fallen leaves of L. tulipifera showed growth inhibitory activity against weed species, Vulpia myuros (L.) C.C.Gmel., Echinochloa crus-galli (L.) P.Beauv., and Lolium multiflorum Lam., under laboratory conditions. The powder of L. tulipifera fresh and fallen leaves also inhibited the germination of E. crus-galli under greenhouse conditions. A potent allelochemical was isolated from fresh and fallen leaf extracts through a bioassay-guided separation process, and was identified as lipiferolide. Lipiferolide inhibited the growth of L. multiflorum and Lepidum sativum in a concentration-dependent manner. This investigation suggests that the leaf waste of L. tulipifera from logging operations and fallen leaves is potentially useful for the purpose of weed control, such as through the use of soil additive materials from leaves or the creation of foliar spray from leaf extracts. The development of weed control materials using L. tulipifera leaf waste may be a means with which to minimize waste, reducing environmental impacts and economic concerns.

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Wajeepeptin, a Cytotoxic and Antitrypanosomal Cyclic Depsipeptide from a Marine Moorena sp. Cyanobacterium

Kurisawa N., Jeelani G., Nozaki T., Agusta A.L., Suenaga K., Iwasaki A.

Journal of Natural Products 87 ( 7 ) 1838 - 1843 2024.07

ISSN 01633864

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Structure–activity relationship studies on iezoside, a highly potent Ca2+ ATPase inhibitor

Kurisawa N., Teranuma K., Noto A., Iwasaki A., Kabashima Y., Nakajima R., Toyoshima C., Suenaga K.

Bulletin of the Chemical Society of Japan 97 ( 7 ) 2024.07

ISSN 00092673

Iezoside (1a) is a novel, potent sarco-/endoplasmic reticulum Ca2+ ATPase (SERCA) inhibitor from marine cyanobacterium. This paper describes the synthesis of comprehensive iezoside (1a) analogs containing C-18/19 diastereomers, simplified analogs without the peptide unit, and aglycones. Evaluations of the antiproliferative activities against cancer cells and SERCA inhibitory activities of the synthesized analogs revealed how the absolute configurations at C-18/19, peptide, and the sugar unit contribute to each bioactivity.

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Allelopathy and Allelochemicals in Chamaecyparis obtusa Leaves for the Development of Sustainable Agriculture

Kato-Noguchi H., Mori K., Iwasaki A., Suenaga K.

Agronomy 14 ( 7 ) 2024.07

Chamaecyparis obtusa (Siebold et Zucc.) Endl. is cultivated in the temperate region of East Asia for its high-quality and profitable timber. The timber-processing industry produces a large amount of waste, such as tree bark, branches, and leaves, and finding ways to minimize such waste is economically and environmentally efficient. In the present study, the allelopathic activity and allelochemicals of the C. obtusa leaves were investigated to develop potential application methods. C. obtusa leaves were phytotoxic and associated leaf extracts significantly suppressed the growth of the weeds; Echinochloa crus-galli, Phleum pratense and Lolium multiflorum under laboratory conditions. The leaf powder applied onto the soil surface also suppressed the germination of E. crus-galli and P. pratense under greenhouse conditions. Hinokiic acid and (+)-dihydrosesamin were isolated from the leaves and structurally identified. Both compounds suppressed the growth of cress and P. pratense in a concentration dependent manner. When the leaves of C. obtua were applied as a soil additive, hinokiic acid and (+)-dihydrosesamin in the leaves potentially cause the growth inhibitory activity by leaching into the soil. These experiments showed that the leaves and the leaf extracts of C. obtusa are phytotoxic. These experiments also demonstrated that the leaves and the leaf extracts of C. obtusa have growth inhibitory potential against several plant species, and the leaves produce allelochemicals. Therefore, the leaves and leaf extracts of C. obtusa may be useful for weed suppression purposes. The leaf biomass of C. obtusa is frequently large and the timber processing industry produces significant leaf waste. The development of weed control products using waste leaves may be a solution to minimize the timber processing waste to reduce environmental impact and provide economic value. However, leaf material should be evaluated for weed suppression and herbicidal activity as a soil additive and also possible as a foliar spray under field conditions.

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Kagimminols A and B, Cembrene-Type Diterpenes from an Okeania sp. Marine Cyanobacterium

Ebihara A., Taguchi R., Jeelani G., Nozaki T., Suenaga K., Iwasaki A.

Journal of Natural Products (Journal of Natural Products) 87 ( 4 ) 1116 - 1123 2024.04

ISSN 01633864

Kagimminols A (1) and B (2), new cembrene-type diterpenoids, were isolated from an Okeania sp. marine cyanobacterium. By combining DP4 analysis with an efficient NMR chemical shift calculation protocol, we clarified the relative configurations of 1 and 2 without consuming precious natural products. We determined the absolute configurations by a comparison of theoretical electronic circular dichroism (ECD) spectra with experimental spectra, and the absolute configuration of 1 was verified experimentally. Finally, we found that 1 and 2 showed selective growth-inhibitory activity against the causative agent of human African trypanosomiasis. This study exemplifies that computational chemistry is an efficient tool for clarifying the configurations of natural products possessing tautomers in equilibrium.

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Isolation and structure determination of a new analog of polycavernosides from marine Okeania sp. cyanobacterium

Umeda K., Kurisawa N., Jeelani G., Nozaki T., Suenaga K., Iwasaki A.

Beilstein Journal of Organic Chemistry (Beilstein Journal of Organic Chemistry) 20 645 - 652 2024

Polycavernoside E (1), a new polycavernoside analog, was isolated from a marine Okeania sp. cyanobacterium. The relative configuration was elucidated primarily by analyzing the two dimensional nuclear magnetism resonance (2D NMR) data. The absolute configuration was clarified by comparing the electronic circular dichroism (ECD) data of 1 with those of known analogs. Polycavernoside E (1) exhibited moderate antitrypanosomal activity against Trypanosoma brucei rhodesiense. Furthermore, the isolation of polycavernoside E (1) from marine cyanobacteria provides additional evidence that marine cyanobacteria, and not red algae, are responsible for the biosynthesis of polycavernosides.

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Allelopathic potential of Oldenlandia corymbosa and identification of its allelopathic substances

Kyaw E.H., Hossen K., Iwasaki A., Suenaga K., Kato-Noguchi H.

Plant Biosystems (Plant Biosystems) 158 ( 3 ) 394 - 403 2024

ISSN 11263504

The use of allelopathy developed as an alternative practice for weed management in agriculture. Oldenlandia corymbosa is an annual herb and notable for being applied in folk medicine. Its diverse range of pharmacological properties and several bioactive substances have been well reported. Nevertheless, the allelopathic potential of O. corymbosa has not yet been documented. Hence, we aim to explore the allelopathy of O. corymbosa for weed control purposes. The extracts of O. corymbosa were tested to determine their effects on the seedling growth of six tested species. Significant reductions in the growth of seedling were exhibited as the plant extract concentrations increased. The plant extracts of O. corymbosa were separated in several chromatography steps; two active substances isolated and characterized as hedyotiscone A and B. Hedyotiscone A and B significantly restricted the growth of cress seedling at concentrations higher than 0.3 mM. The I50 values of hedyotiscone A and B for the cress seedlings ranged from 0.023 to 0.131 mM and 0.167 to 0.810 mM, respectively. The inhibitory activity against cress seedlings indicates that hedyotiscone A and B contribute to the allelopathic effects and may be responsible for the allelopathic potential of O. corymbosa.

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Isolation and Structure Determination of Akunolides, Macrolide Glycosides from a Marine Okeania sp. Cyanobacterium

Umeda K., Iwasaki A., Taguchi R., Kurisawa N., Jeelani G., Nozaki T., Suenaga K.

Journal of Natural Products (Journal of Natural Products) 86 ( 11 ) 2529 - 2538 2023.11

ISSN 01633864

Akunolides A (1), B (2), C (3), and D (4), new macrolide glycosides, were isolated from a marine Okeania sp. cyanobacterium. Their structures were elucidated by spectroscopic analyses and derivatization reactions. Akunolides A-D (1-4) are classified as 16-membered macrolide glycosides, which are relatively rare structures for marine cyanobacterium-derived natural products. Akunolides A-D (1-4) showed moderate antitrypanosomal activities against Trypanosoma brucei rhodesiense, with IC50 values ranging from 11 to 14 μM. Furthermore, akunolides A (1) and C (3) exhibited no cytotoxicity against normal human WI-38 cells even at a concentration of 150 μM.

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Fumagillin inhibits growth of the enteric protozoan parasite Entamoeba histolytica by covalently binding to and selectively inhibiting methionine aminopeptidase 2

Watanabe N., Saito-Nakano Y., Kurisawa N., Otomo K., Suenaga K., Nakano K., Nozaki T.

Antimicrobial Agents and Chemotherapy (Antimicrobial Agents and Chemotherapy) 67 ( 11 ) 2023.11

ISSN 00664804

Amebiasis is an important cause of morbidity and mortality worldwide, and caused by infection with the protozoan parasite Entamoeba histolytica. Metronidazole is currently the first-line drug despite adverse effects and concerns on the emergence of drug resistance. Fumagillin, a fungal metabolite from Aspergillus fumigatus, and its structurally related natural and synthetic compounds have been previously explored as potential anti-angiogenesis inhibitors for cancers, anti-microbial, and anti-obese compounds. Although fumagillin was used for human amebiasis in clinical trials in 1950s, the mode of action of fumagillin remains elusive until now. In this report, we showed that fumagillin covalently binds to methionine aminopeptidase 2 (MetAP2) and non-covalently but abundantly binds to patatin family phospholipase A (PLA). Susceptibility against fumagillin of the amebic strains in which expression of E. histolytica MetAP2 (EhMetAP2) gene was silenced increased compared to control strain. Conversely, overexpression of EhMetAP2 mutants that harbors amino acid substitutions responsible for resistance to ovalicin, a fumagillin analog, in human MetAP2, also resulted in decrease in fumagillin susceptibility. In contrast, neither gene silencing nor overexpression of E. histolytica PLA (EhPLA) affected fumagillin susceptibility. These data suggest that EhPLA is not essential and not the target of fumagillin for its amebicidal activity. Taken together, our data have demonstrated that EhMetAP2 is the primary target for amebicidal activity of fumagillin, and EhMetAP2 represents a rational explorable target for the development of alternative therapeutic agents against amebiasis.

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Total synthesis of acetylene-containing lipopeptides odookeanynes A and B

Lo Y.H., Umeda K., Kurisawa N., Jeelani G., Nozaki T., Suenaga K.

Tetrahedron Letters (Tetrahedron Letters) 130 2023.10

ISSN 00404039

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Total Synthesis of Ikoamide, a Highly N-Methylated Antimalarial Lipopeptide

Lo Y.H., Iwasaki A., Suenaga K.

Journal of Organic Chemistry (Journal of Organic Chemistry) 88 ( 15 ) 10565 - 10573 2023.08

ISSN 00223263

Ikoamide (1) is a highly N-methylated antimalarial lipopeptide that was isolated from a marine cyanobacterium, an Okeania sp. in 2018, which shows strong antimalarial activity without cytotoxicity against human cancer cell lines. To establish a synthetic method for obtaining enough ikoamide for its biological evaluations, we have established a total synthesis of ikoamide. The synthetic method presented here lays the foundation for the development of novel ikoamide analogues, which may lead to a discovery of pharmaceutically unique antimalarial drug leads.

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Differentiation-Promoting Effects of Okeaniamides A and B from an Okeania sp. Marine Cyanobacterium on Preadipocytes

Ozaki K., Asato Y., Natsume N., Tojo S., Sumimoto S., Iwasaki A., Suenaga K., Teruya T.

Journal of Natural Products (Journal of Natural Products) 86 ( 6 ) 1564 - 1570 2023.06

ISSN 01633864

The linear lipopeptides okeaniamide A (1) and okeaniamide B (2) were isolated from an Okeania sp. marine cyanobacterium collected in Okinawa. The structures of these compounds were established by spectroscopic analyses, and the absolute configurations were elucidated based on a combination of chemical degradations, Marfey’s analysis, and derivatization reactions. Okeaniamide A (1) and okeaniamide B (2) dose-dependently promoted the differentiation of mouse 3T3-L1 preadipocytes in the presence of insulin.

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Unique Initiation and Termination Mechanisms Involved in the Biosynthesis of a Hybrid Polyketide-Nonribosomal Peptide Lyngbyapeptin B Produced by the Marine Cyanobacterium Moorena bouillonii

Kudo F., Chikuma T., Nambu M., Chisuga T., Sumimoto S., Iwasaki A., Suenaga K., Miyanaga A., Eguchi T.

ACS Chemical Biology (ACS Chemical Biology) 18 ( 4 ) 875 - 883 2023.04

ISSN 15548929

Lyngbyapeptin B is a hybrid polyketide-nonribosomal peptide isolated from particular marine cyanobacteria. In this report, we carried out genome sequence analysis of a producer cyanobacterium Moorena bouillonii to understand the biosynthetic mechanisms that generate the unique structural features of lyngbyapeptin B, including the (E)-3-methoxy-2-butenoyl starter unit and the C-terminal thiazole moiety. We identified a putative lyngbyapeptin B biosynthetic (lynB) gene cluster comprising nine open reading frames that include two polyketide synthases (PKSs: LynB1 and LynB2), four nonribosomal peptide synthetases (NRPSs: LynB3, LynB4, LynB5, and LynB6), a putative nonheme diiron oxygenase (LynB7), a type II thioesterase (LynB8), and a hypothetical protein (LynB9). In vitro enzymatic analysis of LynB2 with methyltransferase (MT) and acyl carrier protein (ACP) domains revealed that the LynB2 MT domain (LynB2-MT) catalyzes O-methylation of the acetoacetyl-LynB2 ACP domain (LynB2-ACP) to yield (E)-3-methoxy-2-butenoyl-LynB2-ACP. In addition, in vitro enzymatic analysis of LynB7 revealed that LynB7 catalyzes the oxidative decarboxylation of (4R)-2-methyl-2-thiazoline-4-carboxylic acid to yield 2-methylthiazole in the presence of Fe2+ and molecular oxygen. This result indicates that LynB7 is responsible for the last post-NRPS modification to give the C-terminal thiazole moiety in lyngbyapeptin B biosynthesis. Overall, we identified and characterized a new marine cyanobacterial hybrid PKS-NRPS biosynthetic gene cluster for lyngbyapeptin B production, revealing two unique enzymatic logics.

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Isolation of Hennaminal and Isolation and Total Synthesis of Hennamide, Pyrrolinone Compounds from the Marine Cyanobacterium Rivularia sp.

Takahashi H., Iwasaki A., Ebihara A., Taguchi R., Jeelani G., Nozaki T., Suenaga K.

Organic Letters (Organic Letters) 25 ( 14 ) 2400 - 2404 2023.04

ISSN 15237060

Two new natural products were isolated from the marine cyanobacterium Rivularia sp. collected in Japan. Hennaminal possesses a very rare functional group, β,β-diamino unsaturated ketone, which has only been found in bohemamine-type natural products so far. Hennamide possesses a reactive N-acyl pyrrolinone moiety, which induces self-dimerization. The isolation and structure determination supported by computational chemistry and total synthesis, as well as the antitrypanosomal activities of hennaminal and hennamide are described.

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Allelopathic Potential of Marsdenia tenacissima (Roxb.) Moon against Four Test Plants and the Biological Activity of Its Allelopathic Novel Compound, 8-Dehydroxy-11β-O-Acetyl-12β-O-Tigloyl-17β-Marsdenin

Moh S.M., Kurisawa N., Suenaga K., Kato-Noguchi H.

Plants (Plants) 12 ( 8 ) 2023.04

Plant parts and extracts that are rich in bioactive substances with allelopathic potential can be explored as a possible alternative to herbicides for natural weed control in sustainable agriculture. In the present study, we investigated the allelopathic potential of Marsdenia tenacissima leaves and its active substances. Aqueous methanol extracts of M. tenacissima showed significant inhibitory activities against the growth of lettuce (Lactuca sativa L.), alfalfa (Medicago sativa L.), timothy (Phleum pratense L.), and barnyard grass (Echinochloa crusgalli (L.) Beauv.). The extracts were purified through various chromatography steps, and one active substance was isolated and determined by spectral data to be a novel compound, assigned as steroidal glycoside 3 (8-dehydroxy-11β-O-acetyl-12β-O-tigloyl-17β-marsdenin). Steroidal glycoside 3 significantly inhibited the seedling growth of cress at a concentration of 0.03 mM. The concentrations needed for 50% growth inhibition of the cress shoots and roots were 0.25 and 0.03 mM, respectively. These results suggest that steroidal glycoside 3 may be responsible for the allelopathy of M. tenacissima leaves.

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Isolation and Identification of Plant-Growth Inhibitory Constituents from Polygonum chinense Linn and Evaluation of Their Bioherbicidal Potential

Lun T.L., Iwasaki A., Suenaga K., Kato-Noguchi H.

Plants (Plants) 12 ( 7 ) 2023.04

Polygonum chinense Linn. is a medicinal and invasive plant that belongs to the family Polygonaceae. The pharmacological activities and phytochemical constituents of Polygonum chinense are well reported, but the allelopathic effects and potent allelopathic substances of P. chinense remain to be investigated. Hence, this experiment was conducted to separate and characterize potentially allelopathic substances from an extract of the Polygonum chinense plant. The Polygonum chinense plant extracts highly suppressed the growth of cress (Lepidium sativum L.), lettuce (Lactuca sativa L.), barnyard grass (Echinochloa crusgalli (L.) P. Beauv.), and timothy grass (Phleum pratense L.) seedlings in a species- and concentration-dependent way. Two active substances were separated using a series of purification procedures and determined through spectral analysis as (−)-3-hydroxy-β-ionone and (−)-3-hydroxy-7,8-dihydro-β-ionone. These two compounds significantly suppressed the seedling growth of Lepidium sativum (cress) at concentrations of 0.01 and 1 mM, respectively. The extract concentrations necessary for 50% growth inhibition (I50 values) of the cress hypocotyls and roots were 0.05 and 0.07 mM for (−)-3-hydroxy-β-ionone, respectively, and 0.42 and 1.29 mM for (−)-3-hydroxy-7,8-β-ionone, respectively. These findings suggest that these two compounds are in charge of the inhibitory effects of the Polygonum chinense extract and may serve as weed control agents.

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Allelopathic Substances of Osmanthus spp. for Developing Sustainable Agriculture

Kato-Noguchi H., Hamada Y., Kojima M., Kumagai S., Iwasaki A., Suenaga K.

Plants (Plants) 12 ( 2 ) 2023.01

Osmanthus fragrans Lour. has been cultivated for more than 2500 years because of the fragrance and color of the flowers. The flowers and roots have been used in tea, liquors, foods, and traditional Chinese medicine. The species contains more than 180 compounds including terpenoids, phenylpropanoids, polyphenols, flavonoids, and sterols. However, there has been limited information available on the allelopathic properties and allelopathic substances of O. fragrans. We investigated the allelopathy and allelopathic substances of O. fragrans and Osmanthus heterophyllus (G.Don) P.S. Green, as well as Osmanthus × fortunei Carrière, which is the hybrid species between O. fragrans and O. heterophyllus. The leaf extracts of O. fragrans, O. heterophyllus, and O. × fortunei suppressed the growth of cress (Lepidium sativum L.), alfalfa (Medicago sativa L.), Lolium multiflorum Lam., and Vulpia myuros (L.) C.C.Gmel with the extract concentration dependently. The extract of the hybrid species O. × fortune was the most active among the extracts. The main allelopathic substances of O. × fortunei and O. fragrans were isolated and identified as (+)-pinoresinol and 10-acetoxyligustroside, respectively. (+)-Pinoresinol was also found in the fallen leaves of O. × fortunei. Both compounds showed an allelopathic activity on the growth of cress and L. multiflorum. On the other hand, several allelopathic substances including (+)-pinoresinol may be involved in the allelopathy of O. heterophyllus. O. fragrans, O. heterophyllus, and O. × fortunei are evergreen trees. but their senescent leaves fall and cover the soil under the trees. It is possible that those allelopathic substances are liberated through the decomposition process of the leaves into their rhizosphere soil, and that they accumulate in the soil and provide a competitive advantage to the species through the inhibition of the growth of the neighboring competing plants. Therefore, the leaves of these Osmanthus species are allelopathic and potentially useful for weed management options in some agriculture settings to reduce commercial herbicide dependency for the developing sustainable agriculture systems.

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Assessment of the Phytotoxic Potential of Dregea volubilis (L.f.) Benth. ex Hook.f. and Identification of its Phytotoxic Substances for Weed Control

Kyaw E.H., Iwasaki A., Suenaga K., Kato-Noguchi H.

Agriculture (Switzerland) (Agriculture (Switzerland)) 12 ( 11 ) 2022.11

The phytotoxic potential of plants and the effect of their active components on another plant species is being explored as a potential alternative to synthetic herbicides for weed control. In the current study, we investigated the phytotoxic potential of the leaves of Dregea volubilis (L.f.) Benth. ex Hook.f. against four test plants [timothy (Phleum pratense L.), barnyard grass (Echinochloa crus-galli (L.) P. Beauv), lettuce (Lactuca sativa L.), and alfalfa (Medicago sativa L.)] and observed significant growth inhibition on those plants at concentrations >3 mg D.W. equivalent extract mL−1. A bioassay-governed purification of the D. volubilis extracts using different chromatography phases produced two growth inhibitory compounds, 3-hydroxy-α-ionone (compound 1) and 5-hydroxy-3,4-dimethyl-5-pentylfuran-2(5H)-one (compound 2). The compounds retarded the growth of barnyard grass and cress (Lepidium sativum L.) with I50 (concentration required for 50% growth suppression) values ranging from 0.098 to 0.450 mM for 3-hydroxy-α-ionone and 0.029 to 0.420 mM for 5-hydroxy-3,4-dimethyl-5-pentylfuran-2(5H)-one. Thus, the extracts and identified compounds may have the possibility to be utilized as bioagents for weed control.

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Two Allelopathic Substances from Plumbago rosea Stem Extracts and Their Allelopathic Effects

Lun T.L., Iwasaki A., Suenaga K., Kato-Noguchi H.

Agronomy (Agronomy) 12 ( 9 ) 2022.09

The plant Plumbago rosea Linn., belonging to the Plumbaginaceae family, is an important medicinal herb distributed in part of Southeast Asia, and there are many reports of its pharmacological properties. However, the allelopathic activities of P. rosea have not been examined. Thus, the present study was conducted to assess the allelopathic activity of P. rosea and to identify its allelopathic substances. The aqueous methanol stem extract of P. rosea significantly suppressed the seedling growth of barnyard grass (Echinochloa crus-galli L. P. Beauv.), Italian ryegrass (Lolium multiflorum Lam.), timothy (Phleum pretense L.), cress (Lepidium sativum L.), lettuce (Lactuca sativa L.), and alfalfa (Medicago sativa L.). The extract of P. rosea was then purified through chromatographic steps, and two active substances were isolated and determined as 7,4′,5′-tri-O-methyl dihydroquercetin and 7,4′,5′-tri-O-methylampelopsin. The two compounds significantly inhibited the seedling growth of cress, with 7,4′,5′-tri-O-methylampelopsin showing a greater inhibitory effect than 7,4′,5′-tri-O-methyl dihydroquercetin. This result may be due to the 3′-OH group in 7,4′,5′-tri-O-methylampelopsin. The effective concentrations of both compounds required for 50% growth inhibition (EC50 values) of cress seedlings were 0.24 mM and 0.59 mM for root and shoot, and 0.07 mM and 0.21 mM, respectively. These findings suggest that the two compounds may contribute to the allelopathic effect of P. rosea and could be used as a natural source of allelopathic substances.

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Phytotoxic Effects of Senna garrettiana and Identification of Phytotoxic Substances for the Development of Bioherbicides

Krumsri R., Iwasaki A., Suenaga K., Kato-Noguchi H.

Agriculture (Switzerland) (Agriculture (Switzerland)) 12 ( 9 ) 2022.09

Phytotoxic substances in plants that may serve as alternative natural herbicides for controlling weeds are required for sustainable agriculture. We explored the phytotoxic activities of aqueous methanol extracts of Senna garrettiana (Craib) Irwin & Barneby leaves and the active substances they contain. The results revealed that the S. garrettiana leaf extracts had significant phytotoxic effects on three dicotyledons (Lepidium sativum L., Lactuca sativa L., and Medicago sativa L.) and two monocotyledons (Phleum pratense L. and Lolium multiflorum Lam.). An bioassay-guided isolation process yielded three active substances; caffeic acid, methyl caffeate, and (S)-6-hydroxymellein inhibited the seed germination, seedling growth, and biomass accumulation of L. sativum in a concentration-dependent manner. Based on the concentration required for 50% growth inhibition (IC50), (S)-6-hydroxymellein had the highest inhibitory effects on L. sativum in all test parameters, followed by methyl caffeate and caffeic acid. The L. sativum roots were the most susceptible to (S)-6-hydroxymellein (IC50 = 383 µM) and caffeic acid (IC50 = 2627 µM), whereas methyl caffeate (IC50 = 1361 µM) had the greatest effect on the L. sativum shoots. Thus, three isolated compounds may explain the phytotoxic effects of the S. garrettiana extracts. Consequently, caffeic acid, methyl caffeate, and (S)-6-hydroxymellein could be potential candidates for the future production of bioherbicides.

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Isolation and Total Synthesis of Beru'amide, an Antitrypanosomal Polyketide from a Marine Cyanobacterium Okeania sp.

Taguchi R., Iwasaki A., Ebihara A., Jeelani G., Nozaki T., Suenaga K.

Organic Letters (Organic Letters) 24 ( 25 ) 4710 - 4714 2022.07

ISSN 15237060

A 68 μg amount of an acyclic polyketide, named beru'amide, was isolated from a marine cyanobacterium Okeania sp. Beru'amide contains six unique moieties in its relatively small skeleton. By applying several cutting-edge techniques, including DFT-based chemical shift calculations, we achieved the structure determination and the total synthesis of this highly functionalized scarce natural product. Furthermore, beru'amide was shown to have strong antitrypanosomal activity. 2022 American Chemical Society.

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Isolation of Caldorazole, a Thiazole-Containing Polyketide with Selective Cytotoxicity under Glucose-Restricted Conditions

Ohno O., Iwasaki A., Same K., Kudo C., Aida E., Sugiura K., Sumimoto S., Teruya T., Tashiro E., Simizu S., Matsuno K., Imoto M., Suenaga K.

Organic Letters (Organic Letters) 24 ( 25 ) 4547 - 4551 2022.07

ISSN 15237060

Caldorazole (1) was isolated from the marine cyanobacterium Caldora sp. collected on Ishigaki Island, Okinawa, Japan. Its structure was determined to be a new polyketide that contained two thiazole rings and an O-methylenolpyruvamide moiety. Caldorazole (1) showed strong cytotoxicity toward tumor cells that had been seeded at a high density. Cell death induced by 1 in HeLa and A431 cells was also observed only in the presence of the glycolysis blocker 2-deoxy-d-glucose (2DG). Co-treatment with 1 and 2DG remarkably decreased ATP levels in these cells. Furthermore, 1 selectively inhibited complex I in the mitochondrial respiratory chain. Thus, 1 was demonstrated to exert cytotoxicity toward human tumor cells by blocking mitochondrial respiration. 2022 American Chemical Society.

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Allelopathic Activity of a Novel Compound, 5,6-Dihydrogen-11α-O-acetyl-12β-O-tigloyl-17β-marsdenin, and a Known Steroidal Glycoside from the Leaves of Marsdenia tenacissima (Roxb.) Moon

Moh S.M., Iwasaki A., Suenaga K., Kato-Noguchi H.

Agronomy (Agronomy) 12 ( 7 ) 2022.07

Medicinal plants are rich sources of bioactive substances that can be used to develop environmentally friendly weed control alternatives. Marsdenia tenacissima (Roxb.) Moon is a traditional medicinal plant well known for its pharmacological activities and several bioactive compounds. However, its allelopathy and related substances have not been reported. Hence, the present study was conducted to explore the allelopathic potential and substances from M. tenacissima leaves. Aqueous methanol extracts of M. tenacissima showed significant inhibitory activities against the growth of cress (Lepidium sativum L.) and Italian ryegrass (Lolium multiflorum Lam.). The extracts were purified through various chromatography steps, and two allelopathic substances were isolated and determined by spectral data to be steroidal glycoside 1 (5,6-dihydrogen-11α-O-acetyl-12β-O-tigloyl-17β-marsdenin), a novel compound, and steroidal glycoside 2 (5,6-dihydrogen-11α,12β-di-O-tigloyl-17β-marsdenin). Both compounds significantly inhibited the growth of cress seedlings. Steroidal glycoside 1 showed 1.6-and 4-times greater growth inhibitory potential against the cress shoots and roots than steroidal glycoside 2. The concentrations needed for 50% growth inhibition of the cress seedling shoots and roots were 0.46 and 0.03 mM for steroidal glycoside 1, respectively, and 0.74 and 0.12 mM for steroidal glycoside 2, respectively. Therefore, these results suggest that steroidal glycosides 1 and 2 may be responsible for the allelopathy of the M. tenacissima leaves.

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Structural Determination, Total Synthesis, and Biological Activity of Iezoside, a Highly Potent Ca2+-ATPase Inhibitor from the Marine Cyanobacterium Leptochromothrix valpauliae

Kurisawa N., Iwasaki A., Teranuma K., Dan S., Toyoshima C., Hashimoto M., Suenaga K.

Journal of the American Chemical Society (Journal of the American Chemical Society) 144 ( 24 ) 11019 - 11032 2022.06

ISSN 00027863

Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) is a membrane protein on the endoplasmic reticulum (ER) that transports Ca2+ from the cytosol into the ER. As its function is associated with various biological phenomena, SERCA has been recognized as a promising druggable target. Here, we report the second-strongest SERCA-inhibitory compound known to date, which we isolated from the marine cyanobacterium Leptochromothrix valpauliae and named iezoside (1). The structure of iezoside (1) is fundamentally different from that of any other SERCA inhibitor, and its potency is the strongest among marine natural products (Ki 7.1 nM). In this article, we report our comprehensive analysis of iezoside (1), which covers its isolation, structural characterization supported by density functional theory (DFT) calculations and statistical analysis, total synthesis, and clarification of the mode of action of its potent antiproliferative activity (IC50 6.7 ± 0.4 nM against HeLa cells).

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Allelopathy of the Medicinal Plant Dregea volubilis (L.f.) Benth. ex Hook.f. and Its Phytotoxic Substances with Allelopathic Activity

Kyaw E.H., Iwasaki A., Suenaga K., Kato-Noguchi H.

Agronomy (Agronomy) 12 ( 2 ) 2022.02

Allelopathic plants and their related phytotoxic chemicals have been explored as alter-natives for environmentally friendly weed management. Dregea volubilis (L.f.) Benth. ex Hook.f., a woody vine, is well-known for its uses in various therapeutic treatments, and several bioactive compounds have been isolated from this species. However, to date, no phytotoxic substances from D. volubilis have been reported. Hence, in this research, we aimed to investigate the allelopathic effect of D. volubilis and characterize its phytotoxic substances. Extracts of D. volubilis exhibited significant inhibitory activity against the seedling growth of Italian ryegrass (Lolium multiflorum Lam.) and cress (Lepidium sativum L.). The extracts were purified through several chromatography steps, yielding two phytotoxic substances, and using spectroscopy, their structures were determined as dehydrovomi-foliol and loliolide. The compounds inhibited the Italian ryegrass and cress seedlings with the I50 (concentrations needed for 50% inhibition) values ranging from 0.022 to 0.102 mM, for loliolide and 3.24–4.60 mM, for dehydrovomifoliol. These results suggest that both phytotoxic compounds might be responsible for the allelopathy of D. volubilis, and they may be released into the soil through the decomposition of the D. volubilis leaf and probably act as allelopathic active substances. Therefore, the extracts of D. volubilis and its related phytotoxic compounds may be applied as biological agents for controlling weeds.

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Assessment of Allelopathic Potential of Senna garrettiana Leaves and Identification of Potent Phytotoxic Substances

Krumsri R., Iwasaki A., Suenaga K., Kato-Noguchi H.

Agronomy (Agronomy) 12 ( 1 ) 2022.01

Senna garrettiana (Craib) Irwin & Barneby (Fabaceae) is a medicinal plant known to be rich in biologically active compounds that could be exploited to produce bioherbicides. The present study was conducted to explore the allelopathic potential and phytotoxic substances of S. garrettiana. Extracts of S. garrettiana leaves were found to significantly inhibit the growth of Lepidium sativum L. and Echinochloa crus-galli (L.) P. Beauv. (p ≤ 0.05). The phytotoxic substances were isolated and identified as vanillic acid and ferulic acid by bioassay-directed fractionation and spectral data analysis. The two compounds were shown to significantly inhibit the seed germination, seedling growth, and dry biomass of L. sativum. Based on the concentration required for 50% growth inhibition (defined as IC50), the roots of L. sativum were the most sensitive to the compounds, and the inhibitory effect of ferulic acid (IC50 = 0.62 mM) was >1.3 times more potent than that of vanillic acid (IC50 = 0.82 mM). In addition, a mixture of the two compounds (0.3 mM) resulted in synergistic inhibitory activity against the L. sativum roots compared with the individual compounds. These results suggest that the extracts of S. garrettiana leaves and their phytotoxic compounds have potential as candidate natural herbicides.

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Allelopathy and Allelopathic Substances of Fossil Tree Species Metasequoia glyptostroboides

Matuda Y., Iwasaki A., Suenaga K., Kato-Noguchi H.

Agronomy (Agronomy) 12 ( 1 ) 2022.01

Metasequoia glyptostroboides Hu et W.C. Cheng is one of the oldest living conifer species, and it has remained unchanged for millions of years compared to its fossils from the Cretaceous period. The species are cultivated in the parks, gardens, and roadsides in many countries. We investigated the allelopathy and allelopathic substances in fallen leaves of M. glyptostroboides. An aqueous methanol extract of the fallen leaves inhibited the growth of cress (Lepidium sativum L.), lettuce (Lactuca sativa L.), alfalfa (Medicago sativa L.), Lolium multiflorum Lam., Phleum pretense L., and Vulpia myuros (L.) C.C.Gmel. The extract was then purified by several chromatographic steps, and two allelopathic substances were isolated and determined by spectral data to be (+)-rhododendrol and 9-epi-blumenol C. The compound inhibited the growth of cress and L. multiflorum. M. glyptostroboides is a deciduous perennial tree, and accumulation of its fallen leaves occur on the soil under the trees. Therefore, those allelopathic substances in the fallen leaves may be liberated into the rhizo-sphere soil during the decomposition process of fallen leaves and provide a competitive advantage for M. glyptostrob through the growth inhibition of competing plant species nearby. Therefore, M. glyptostroboides is allelopathic, and (+)-rhododendrol and 9-epi-blumenol C may be contribute to the allelopathy.

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Total Synthesis of Caldorazole, a Potent Mitochondrial Respiratory Chain Inhibitor without Chiral Centers

Miyamoto Y., Iwasaki A., Fujimura H., Kudo C., Kurisawa N., Ohno O., Suenaga K.

Journal of Organic Chemistry (Journal of Organic Chemistry) 2022

ISSN 00223263

Caldorazole (1) is a novel polyketide that was isolated from a marine cyanobacterium in 2022. It is a unique natural product that exhibits potent inhibitory activity against mitochondrial respiratory chain complex I despite having no chiral centers. To establish a method for obtaining caldorazole without relying on biological resources and for constructing a useful synthetic route for studies of its structure-activity relationship, we achieved the first total synthesis of caldorazole using a convergent synthetic route.

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First Total Synthesis and Structure-Activity Relationship of Iheyamide A, an Antitrypanosomal Linear Peptide Isolated from a Dapissp. Marine Cyanobacterium

Iwasaki A., Teranuma K., Kurisawa N., Rahmawati Y., Jeelani G., Nozaki T., Gerwick W.H., Suenaga K.

Journal of Natural Products (Journal of Natural Products) 84 ( 9 ) 2587 - 2593 2021.09

Accepted, ISSN 01633864

Iheyamide A ( 1 ) is an antitrypanosomal linear peptide isolated from aDapissp. marine cyanobacterium by our group in 2020, and based on structure-activity relationships of its natural analogues, the C-terminal pyrrolinone moiety has been identified as the phamacophore for its antiparasitic activity. Further, we isolated this pyrrolinone moiety by itself as a new natural product from the marine cyanobacterium and named it iheyanone ( 2 ). As expected, iheyanone ( 2 ) showed antitrypanosomal activity, but its potency was weaker than iheyamide A ( 1 ). To clarify more detailed structure-activity relationships, we completed a total synthesis of iheyamide A ( 1 ) along with iheyanone ( 2 ) and evaluated the antitrypanosomal activities of several synthetic intermediates. As a result, we found that the longer the peptide chain, the stronger the antitrypanosomal activity. As iheyamide A ( 1 ) showed selective toxicity againstTrypanosoma brucei rhodesiense, these findings can provide design guidelines for antitrypanosomal drugs.

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Isolation and Total Synthesis of Kinenzoline, an Antitrypanosomal Linear Depsipeptide Isolated from a Marine Salileptolyngbya sp. Cyanobacterium

Kurisawa N., Otomo K., Iwasaki A., Jeelani G., Nozaki T., Suenaga K.

Journal of Organic Chemistry (Journal of Organic Chemistry) 86 ( 18 ) 12528 - 12536 2021.09

ISSN 00223263

Kinenzoline (1), a new linear depsipeptide, was isolated from a marine Salileptolyngbya sp. cyanobacterium. Its structure was elucidated by spectroscopic analyses and degradation reactions. In addition, we achieved a total synthesis of 1 and confirmed its structure. Kinenzoline (1) showed highly selective antiproliferative activity against the causative organism of sleeping sickness, Trypanosoma brucei rhodesiense (IC50 4.5 μM), compared to normal human cells (WI-38, IC50 > 100 μM). Kinenzoline (1) is a promising lead compound for the development of new antitrypanosomal drugs.

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Isolation and Total Synthesis of Bromoiesol sulfates, Antitrypanosomal arylethers from a Salileptolyngbya sp. Marine Cyanobacterium

Ebihara A., Iwasaki A., Miura Y., Jeelani G., Nozaki T., Suenaga K.

Journal of Organic Chemistry (Journal of Organic Chemistry) 86 ( 17 ) 11763 - 11770 2021.09

ISSN 00223263

Bromoiesol sulfates A (1) and B (2), new polyhalogenated aryl sulfates, were isolated from a Salileptolyngbya sp. marine cyanobacterium along with their hydrolyzed compounds, bromoiesols A (3) and B (4). To pick up the candidates of their structures, we used Small Molecule Accurate Recognition Technology (SMART), an artificial intelligence-based structure-prediction tool, and their structures were elucidated on the basis of single-crystal X-ray diffraction analysis of bromoiesols (3 and 4). In addition, to verify the structures, the total synthesis of bromoiesol A sulfate (1) and bromoiesol A (3) was achieved. The bromoiesol family, especially bromoiesols (3 and 4), selectively inhibited the growth of the bloodstream form of Trypanosoma brucei rhodesiense, the causative agent of human African sleeping sickness.

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Phytotoxicity of the novel compound 3-hydroxy-4-oxo-β-dehydroionol and compound 3-oxo-α-ionone from Albizia richardiana (Voigt.) King & Prain

Hossen K., Iwasaki A., Suenaga K., Kato-Noguchi H.

Environmental Technology and Innovation (Environmental Technology and Innovation) 23 2021.08

To protect our environment from the toxic effect of herbicides, it is necessary to reduce the application of synthetic herbicides for controlling weeds in crop fields as well as to increase the use of natural herbicides produced from plant sources. Phytotoxic compounds obtained from plant species have gained attention as an alternate biological method for managing weeds. Albizia richardiana was previously reported to contain a number of phytotoxic substances. Therefore, we carried out this study to investigate more allelopathic substances in Albizia richardiana leaves. Aqueous methanol extracts of Albizia richardiana leaves were significantly inhabited the seedling growth of the two test species (alfalfa and timothy) in a concentration-dependent manner. The two most active substances were separated through different chromatographic steps and characterized as a novel compound 3-hydroxy-4-oxo-β-dehydroionol [(E)-6-hydroxy-3-(3-hydroxybut-1-en-1-yl)-2,4,4-trimethylcyclohexa-2,5-dien-1-one], and compound 3-oxo-α-ionone [3,5,5-trimethyl-4-(3-oxo-1-butenyl)-2-cyclohexen-1-one]. The novel compound 3-hydroxy-4-oxo-β-dehydroionol showed relatively stronger growth inhibitory potential compare to the compound 3-oxo-α-ionone and significantly restricted the seedling growth of crees and timothy. The required concentration for 50% reduction in the growth (I50 values) of the cress and timothy seedlings varied from 63.78 to 141.61 μM for 3-hydroxy-4-oxo-β-dehydroionol and 1059.60 to 1616.10 μM for 3-oxo-α-ionone. The results indicate that these two allelopathic compounds may be responsible for the phytotoxicity of Albizia richardiana leaves.

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Lingaoamide, a cyclic heptapeptide from a Chinese freshwater cyanobacterium Oscillatoria sp.

Iwasaki A., Kurisawa N., Wang T., Li X., Luo H., Zhu C., Patial G., Yan X., He S., Luzzatto-Knaan T., Tian F., Naman C.B., Suenaga K.

Tetrahedron Letters (Tetrahedron Letters) 75 2021.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 00404039

Lingaoamide (1), a new cyclic heptapeptide natural product, was isolated from a freshwater Oscillatoria cyanobacterium. The producing organism was collected in Chinese water spinach paddy farm fields in Lingao County, Hainan, China. The structure of 1 was determined by conventional mass spectrometry, NMR spectroscopy, and chemical degradation studies. Lingaoamide concentration-dependently up-regulates the biogenesis of pro-pathogenic melanin pigments (melanogenesis) in the rice blast fungus, Magnaporthe grisea, when tested in vitro. This molecule also exhibits weak in vitro inhibition (MIC 32 μg/mL) of Gram-negative Pseudomonas aeruginosa and Gram-positive Bacillus pumilus, and does not appear to impact plant growth or immune response in vivo using the model organism, Arabidopsis thaliana.

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Metabolomic characterization of a cf. Neolyngbya cyanobacterium from the south china sea reveals wenchangamide a, a lipopeptide with in vitro apoptotic potential in colon cancer cells

Ding L., Bar-Shalom R., Aharonovich D., Kurisawa N., Patial G., Li S., He S., Yan X., Iwasaki A., Suenaga K., Zhu C., Luo H., Tian F., Fares F., Naman C.B., Luzzatto-Knaan T.

Marine Drugs (Marine Drugs) 19 ( 7 ) 2021.07

Metabolomics can be used to study complex mixtures of natural products, or secondary metabolites, for many different purposes. One productive application of metabolomics that has emerged in recent years is the guiding direction for isolating molecules with structural novelty through analysis of untargeted LC-MS/MS data. The metabolomics-driven investigation and bioassay-guided fractionation of a biomass assemblage from the South China Sea dominated by a marine filamentous cyanobacteria, cf. Neolyngbya sp., has led to the discovery of a natural product in this study, wenchangamide A (1). Wenchangamide A was found to concentration-dependently cause fast-onset apoptosis in HCT116 human colon cancer cells in vitro (24 h IC50 = 38 µM). Untargeted metabolomics, by way of MS/MS molecular networking, was used further to generate a structural proposal for a new natural product analogue of 1, here coined wenchangamide B, which was present in the organic extract and bioactive sub-fractions of the biomass examined. The wenchangamides are of interest for anticancer drug discovery, and the characterization of these molecules will facilitate the future discovery of related natural products and development of synthetic analogues.

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Motobamide, an Antitrypanosomal Cyclic Peptide from a Leptolyngbya sp. Marine Cyanobacterium

Takahashi H., Iwasaki A., Kurisawa N., Suzuki R., Jeelani G., Matsubara T., Sato T., Nozaki T., Suenaga K.

Journal of Natural Products (Journal of Natural Products) 84 ( 5 ) 1649 - 1655 2021.05

ISSN 01633864

Motobamide (1), a new cyclic peptide containing a C-prenylated cyclotryptophan residue, was isolated from a marine Leptolyngbya sp. cyanobacterium. Its planar structure was established by spectroscopic and MS/MS analyses. The absolute configuration was elucidated based on a combination of chemical degradations, chiral-phase HPLC analyses, spectroscopic analyses, and computational chemistry. Motobamide (1) moderately inhibited the growth of bloodstream forms of Trypanosoma brucei rhodesiense (IC50 2.3 μM). However, it exhibited a weaker cytotoxicity against normal human cells (IC50 55 μM).

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Komesuamide and odopenicillatamide, two linear lipopeptides from the marine cyanobacterium Caldora penicillata

Ozaki K., Jinno A., Natsume N., Sumimoto S., Iwasaki A., Suenaga K., Teruya T.

Tetrahedron (Tetrahedron) 85 2021.04

ISSN 00404020

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Isolation and identification of three potential phytotoxic compounds from Chrysopogon aciculatus (Retz.) Trin

Islam M.S., Zaman F., Iwasaki A., Suenaga K., Kato-Noguchi H.

Acta Physiologiae Plantarum (Acta Physiologiae Plantarum) 43 ( 4 ) 2021.04

ISSN 01375881

We conducted an investigation to search for the possibility of phytotoxic compounds and then identify them in C. aciculatus. The aqueous methanol extracts of C. aciculatus imposed a strong suppressive effect on the shoots and roots growth of Medicago sativa and Echinochloa crus-galli. The C. aciculatus extracts were subsequently purified through chromatography and three growth-inhibitory compounds were identified by spectral data as methyl cis-p-coumarate, methyl trans-p-coumarate, and trans-ferulaldehyde. The seedlings growth of Lepidium sativum was suppressed by methyl cis-p-coumarate, methyl trans-p-coumarate, and trans-ferulaldehyde. The I50 values (concentration required for 50% growth inhibition) for the seedling growth of L. sativum ranged from 1.25 to 1.73 mM for methyl cis-p-coumarate, 0.74 to 1.23 mM for methyl trans-p-coumarate, and 1.05 to 1.84 mM for trans-ferulaldehyde. Our finding indicates that methyl cis-p-coumarate, methyl trans-p-coumarate, and trans-ferulaldehyde may contribute to the phytotoxic effects of C. aciculatus.

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Identification and application of bioactive compounds from garcinia xanthochymus hook. For weed management

Rob M.M., Hossen K., Khatun M.R., Iwasaki K., Iwasaki A., Suenaga K., Kato-Noguchi H.

Applied Sciences (Switzerland) (Applied Sciences (Switzerland)) 11 ( 5 ) 1 - 10 2021.03

The allelopathic potential of plant species and their related compounds has been increas-ingly reported to be biological tools for weed control. The allelopathic potential of Garcinia xantho-chymus was assessed against several test plant species: lettuce, rapeseed, Italian ryegrass, and timo-thy. The extracts of G. xanthochymus leaves significantly inhibited all the test plants in a concentra-tion-and species-specific manner. Therefore, to identify the specific compounds involved in the allelopathic activity of the G. xanthochymus extracts, assay-guided purification was carried out and two allelopathic compounds were isolated and identified as methyl phloretate {3-(4-hydroxy-phenyl) propionic acid methyl ester} and vanillic acid (4-hydroxy-3-methoxybenzoic acid). Both of the substances significantly arrested the cress and timothy seedlings growth. I50 values (concentra-tions required for 50% inhibition) for shoots and roots growth of the cress and timothy were 113.6– 104.6 and 53.3–40.5 μM, respectively, for methyl phloretate, and 331.6–314.7 and 118.8–107.4 μM, respectively, for vanillic acid, which implied that methyl phloretate was close to 3-and 2-fold more effective than vanillic acid against cress and timothy, respectively. This report is the first on the presence of methyl phloretate in a plant and its phytotoxic property. These observations suggest that methyl phloretate and vanillic acid might participate in the phytotoxicity of G. xanthochymus extract.

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Phytotoxic activity and growth inhibitory substances from Albizia richardiana (Voigt.) King & Prain

Hossen K., Iwasaki A., Suenaga K., Kato-Noguchi H.

Applied Sciences (Switzerland) (Applied Sciences (Switzerland)) 11 ( 4 ) 1 - 13 2021.02

Albizia richardiana, a fast-growing, large deciduous tree belonging to the Fabaceae family, grows well in hot and humid areas but mainly grows in the tropics of the Old World. The medicinal and other uses of Albizia richardiana are well documented, but the phytotoxic effects of this tree have not yet been investigated. We conducted this study to investigate the phytotoxic activity of Albizia richardiana leaves and to identify growth inhibitory substances for controlling weeds in a sustainable way. Aqueous methanol extracts of Albizia richardiana leaves greatly suppressed the growth of cress and barnyard grass seedlings in a concentration- and species-dependent manner. Two phytotoxic substances were separated using several purification steps and characterized through spectral analysis as dehydrovomifoliol and loliolide. Dehydrovomifoliol and loliolide significantly arrested the seedling growth of cress in the concentrations of 0.1 and 0.01 mM, respectively. The extract concentrations needed for 50% growth inhibition (I50 values) of cress seedlings were 3.16-3.01 mM for dehydrovomifoliol and 0.03-0.02 mM for loliolide. The results suggest that these two allelopathic substances might play a vital role in the phytotoxicity of Albizia richardiana leaves.

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Bioorganic Study ofNew Natural Products Isolatedfrom Marine Cyanobacteria

Iwasaki A., Suenaga K.

Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry (Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry) 79 ( 2 ) 133 - 144 2021.02

ISSN 00379980

Natural products, well known for unique chemical diversity and bioactivity, are the compounds that organisms have acquired in evolutionary history. They have attracted attentions from not only organic chemists but also scientists in related fields and have provided breakthroughs for science. Against this background, we have investigated the secondary metabolites of marine organisms, especially cyanobacteria, and have discovered various novel bioactive compounds. In this account, our recent research activities regarding the isolation, structure determination, total syntheses and biological activities of our novel natural products are described.

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Isolation, structure determination, and total synthesis of hoshinoamide c, an antiparasitic lipopeptide from the marine cyanobacterium caldora penicillata

Suenaga K., Iwasaki A., Ohtomo K., Kurisawa N., Shiota I., Rahmawati Y., Jeelani G., Nozaki T.

Journal of Natural Products (Journal of Natural Products) 2021

ISSN 01633864

© 2020 American Chemical Society. All rights reserved. Hoshinoamide C (1), an antiparasitic lipopeptide, was isolated from the marine cyanobacterium Caldora penicillata. Its planar structure was elucidated by spectral analyses, mainly 2D NMR, and the absolute configurations of the α-amino acid moieties were determined by degradation reactions followed by chiral-phase HPLC analyses. To clarify the absolute configuration of an unusual amino acid moiety, we synthesized two possible diastereomers of hoshinoamide C and determined its absolute configuration based on a comparison of their spectroscopic data with those of the natural compound. Hoshinoamide C (1) did not exhibit any cytotoxicity against HeLa or HL60 cells at 10 μM, but inhibited the growth of the parasites responsible for malaria (IC50 0.96 μM) and African sleeping sickness (IC50 2.9 μM).

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Odookeanynes A and B, Acetylene-Containing Lipopeptides from an Okeania sp. Marine Cyanobacterium

Yamano A., Asato Y., Natsume N., Iwasaki A., Suenaga K., Teruya T.

Journal of Natural Products (Journal of Natural Products) 2021

ISSN 01633864

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Phytotoxic activity of Clerodendrum indicum (L.) Kuntze and its potential phytotoxic substance

Kyaw E.H., Iwasaki A., Suenaga K., Kato-Noguchi H.

Emirates Journal of Food and Agriculture (Emirates Journal of Food and Agriculture) 33 ( 10 ) 884 - 892 2021

ISSN 2079052X

Clerodendrum indicum (L.) Kuntze (Lamiaceae), an annual shrub, is renowned for being used in folk medicine in South Asian countries. Several pharmacological properties and many bioactive secondary metabolites from C. indicum have been well documented. However, the phytotoxic activities and the related phytotoxic substances with the allelopathic activity of C. indicum have not yet been reported. Thus, we explored the phytotoxic activity of C. indicum and identified its phytotoxic substance. In the experiment, the dry C. indicum leaves were extracted with aqueous methanol, and then the filtrate of the extracts was concentrated using a rotary evaporator to obtain crude extracts. The C. indicum crude extracts significantly inhibited the shoots and roots of six target species: alfalfa, cress, lettuce, barnyard grass, Italian ryegrass, and timothy. The inhibition increased when the extract concentration was increased. The crude extracts of C. indicum were separated in several chromatography steps, and a phytotoxic substance was isolated and characterized using spectroscopy as p-coumaric acid. p-Coumaric acid significantly suppressed the growth of lettuce and timothy seedlings at concentrations greater than 0.3 and 1 mM, respectively. The concentrations of p-coumaric acid required for 50% inhibition (I50) of the shoots and roots of lettuce and timothy were 0.65 and 0.17 mM, and 0.81 and 0.67 mM, respectively. This study is the first report on isolating p-coumaric acid in C. indicum. The results, therefore, suggest that p-coumaric acid may partly contribute to the phytotoxic properties of C. indicum.

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Characterization of Macroscopic Colony-Forming Filamentous Cyanobacteria from Okinawan Coasts as Potential Sources of Bioactive Compounds

Nuryadi H., Sumimoto S., Teruya T., Suenaga K., Suda S.

Marine Biotechnology (Marine Biotechnology) 22 ( 6 ) 824 - 835 2020.12

ISSN 14362228

© 2020, Springer Science+Business Media, LLC, part of Springer Nature. Marine macroscopic colony-forming filamentous (MMCFF) cyanobacteria are considered as prolific producers of bioactive compounds. Thus, knowledge of the diversity of MMCFF cyanobacteria as related to bioactive compound production has become very important. However, basic taxonomic studies of MMCFF cyanobacteria are lacking. Many cyanobacterial taxa are still misidentified or undescribed. In this study, a total of 32 cyanobacterial colonies from nine coastal regions of Okinawa Prefecture were investigated for a diversity assessment. A polyphasic approach including morphological and molecular studies based on 16S rRNA gene sequences was performed to characterize Okinawan MMCFF cyanobacteria. Both morphological and molecular phylogenetic results showed that MMCFF cyanobacteria from Okinawan coasts are very diverse. We found morphotypes of Lyngbya-like, Phormidium-like, and Leptolyngbya-like groups among Okinawan cyanobacterial samples. Genetically, samples were distributed in various clades in the phylogenetic tree, including within Moorena, Okeania, Caldora, Neolyngbya, Dapis, as well as several unknown clades. In addition, cytotoxic activities of three samples from Kiyan coast were tested against HeLa cells. All three crude extracts of these samples showed strong cytotoxic activity with IC50 < 1 μg/ml.

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Allelopathic potential and active substances from wedelia chinensis (Osbeck)

Hossen K., Das K.R., Okada S., Iwasaki A., Suenaga K., Kato-Noguchi H.

Foods (Foods) 9 ( 11 ) 2020.11

Wedelia chinensis (Asteraceae) is a wetland herb native to India, China, and Japan. It is a valuable medicinal plant recorded to have pharmaceutical properties. However, the phytotoxic potential of Wedelia chinensis has not yet been examined. Thus, we carried out this study to establish the allelopathic effects of Wedelia chinensis and to identify its phytotoxic substances. Extracts of Wedelia chinensis exhibited high inhibitory activity against the root and shoot growth of cress, alfalfa, rapeseed, lettuce, foxtail fescue, Italian ryegrass, timothy, and barnyard grass. The inhibition was varied with species and was dependent on concentrations. The extracts were separated through several purification steps, and the two effective substances were isolated and characterized as vanillic acid and gallic acid using spectral analysis. Vanillic acid and gallic acid significantly arrested the growth of cress and Italian ryegrass seedlings. The concentrations of vanillic acid and gallic acid needed for 50% inhibition (I50 values) of the seedling growth of the cress and Italian ryegrass were 0.04–15.4 and 0.45–6.6 mM, respectively. The findings suggest that vanillic acid and gallic acid may be required for the growth inhibitory activities of Wedelia chinensis.

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Irijimasides A-E, Macrolide Glycosides from an Okeania sp. Marine Cyanobacterium

Yamano A., Natsume N., Yamada M., Sumimoto S., Iwasaki A., Suenaga K., Teruya T.

Journal of Natural Products (Journal of Natural Products) 83 ( 5 ) 1585 - 1591 2020.05

ISSN 01633864

Copyright © 2020 American Chemical Society and American Society of Pharmacognosy. Irijimasides A-E (1-5), a series of new 14-membered macrolide glycosides, were isolated from a marine cyanobacterium collected in Okinawa. The gross structures of 1-5 were established by spectroscopic analysis, including 2D NMR, while absolute stereostructures were determined based on NOESY spectra, chemical derivatization, and ECD data. All five macrolides suppressed receptor activator of nuclear factor-κB ligand (RANKL)-induced tartrate-resistant acid phosphatase (TRAP) activity in mouse RAW264 macrophage cells, indicating that these compounds inhibit osteoclast formation.

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Iheyamides A-C, Antitrypanosomal Linear Peptides Isolated from a Marine Dapis sp. Cyanobacterium

Kurisawa N., Iwasaki A., Jeelani G., Nozaki T., Suenaga K.

Journal of Natural Products (Journal of Natural Products) 83 ( 5 ) 1684 - 1690 2020.05

ISSN 01633864

© 2020 American Chemical Society and American Society of Pharmacognosy. Iheyamides A (1), B (2), and C (3), new linear peptides, were isolated from a marine Dapis sp. cyanobacterium. Their structures were elucidated by spectroscopic analyses and degradation reactions. Iheyamide A (1) showed moderate antitrypanosomal activities against Trypanosoma brucei rhodesiense and Trypanosoma brucei brucei (IC50 = 1.5 μM), but the other two analogues, iheyamides B (2) and C (3), did not (IC50 > 20 μM, respectively). The structure-activity relationship clarified that an isopropyl-O-Me-pyrrolinone moiety was necessary for the antitrypanosomal activity. Furthermore, the cytotoxicity of 1 against normal human cells, WI-38, was 10 times weaker than its antitrypanosomal activity (IC50 = 18 μM).

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A kaurene-type novel phytotoxic substance in Wedelia chinensis

Rany Das K., Iwasaki A., Suenaga K., Kato-Noguchi H.

Tetrahedron Letters (Tetrahedron Letters) 61 ( 11 ) 2020.03

ISSN 00404039

© 2020 Elsevier Ltd Wedelia chinensis has been widely used as a traditional medicine and several bioactive compounds have been isolated. We investigated phytotoxic property and phytotoxic substances in the species. An aqueous methanol extract of W. chinensis inhibited the growth of roots and shoots of cress. The extracts were then purified by several chromatographic runs with monitoring the inhibitory activity and a phytotoxic substance was isolated. The substance was determined by spectral data to be a novel kaurene-type compound, wedelienone. Wedelienone inhibited the growth of cress and timothy (Phleum pratense L) at concentrations greater than 10–30 μM. These results suggest that wedelienone may contribute to the phytotoxic effects caused by the extracts.

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Isolation and identification of two phytotoxic compounds from the medicinal plant Cassia alata L.

Das K.R., Iwasaki K., Suenaga K., Kato-Noguchi H.

Weed Biology and Management (Weed Biology and Management) 20 ( 1 ) 3 - 11 2020.03

ISSN 14446162

© 2020 Weed Science Society of Japan Cassia alata (Caesalpiniaceae), an ornamental shrub, has many biological properties such as antifungal and antibacterial activities. Several bioactive and phytotoxic compounds have already been isolated from C. alata. Phytotoxic substances from plants have drawn attention as an alternative biological approach to control weeds. Thus, we conducted this research to explore other phytotoxic compounds in C. alata leaves. Aqueous methanol extracts of C. alata leaves strongly inhibited the seedling growth of broccoli, cabbage, cress, radish and rapeseed, in which the level of inhibition correlated with concentration. Two active compounds were isolated through chromatographies and identified using spectral data as (S)-4-(3-hydroxybutyl)phenol [(+)-rhododendrol] and (E)-4-((1R,4R)-4-hydroxy-2,6,6-trimethylcyclohex-2-en-1-yl)but-3-en-2-one [3-hydroxy-α-ionone]. These two active compounds inhibited the growth of cress seedlings in a concentration-dependent manner. The required concentrations for 50% growth inhibition (I50 value) of cress seedlings were 192.0–296.1 μM for (+)-rhododendrol and 132.4–195.3 μM for 3-hydroxy-α-ionone. These results indicate that the two phytotoxic compounds play a part in the phytotoxic activity of C. alata leaves.

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Ikoamide, an Antimalarial Lipopeptide from an Okeania sp. Marine Cyanobacterium

Iwasaki K., Iwasaki A., Sumimoto S., Matsubara T., Sato T., Nozaki T., Saito-Nakano Y., Suenaga K.

Journal of Natural Products (Journal of Natural Products) 83 ( 2 ) 481 - 488 2020.02

ISSN 01633864

Copyright © 2020 American Chemical Society and American Society of Pharmacognosy. An antimalarial lipopeptide, ikoamide, was isolated from an Okeania sp. marine cyanobacterium. Its gross structure was established by spectroscopic analyses, and the absolute configuration was clarified based on a combination of chiral-phase HPLC analyses, spectroscopic analyses, and derivatization reactions. Ikoamide showed strong antimalarial activity with an IC50 value of 0.14 μM without cytotoxicity against human cancer cell lines at 10 μM.

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Tree fern cyathea lepifera may survive by its phytotoxic property

Ida N., Iwasaki A., Teruya T., Suenaga K., Kato-Noguchi H.

Plants (Plants) 9 ( 1 ) 2020.01

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Cyatheaceae (tree ferns) appeared during the Jurassic period and some of the species still remain. Those species may have some morphological and/or physiological characteristics for survival. A tree fern was observed to suppress the growth of other ligneous plants in a tropical forest. It was assumed that the fern may release toxic substances into the forest floor, but those toxic substances have not yet been identified. Therefore, we investigated the phytotoxicity and phytotoxic substances of Cyathea lepifera (J. Sm. ex Hook.) Copel. An aqueous methanol extract of C. lepifera fronds inhibited the growth of roots and shoots of dicotyledonous garden cress (Lepidum sativum L.), lettuce (Lactuca sativa L.), and alfalfa (Medicago sativa L.), and monocotyledonous ryegrass (Lolium multiflorum Lam.), timothy (Phleum pratense L.), and barnyardgrass (Echinochloa crus-galli (L.) P. Beauv.). The results suggest that C. lepifera fronds may have phytotoxicity and contain some phytotoxic substances. The extract was purified through several chromatographic steps during which inhibitory activity was monitored, and p-coumaric acid and (-)-3-hydroxy-β-ionone were isolated. Those compounds showed phytotoxic activity and may contribute to the phytotoxic effects caused by the C. lepifera fronds. The fronds fall and accumulate on the forest floor through defoliation, and the compounds may be released into the forest soils through the decomposition process of the fronds. The phytotoxic activities of the compounds may be partly responsible for the fern’s survival.

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Phytotoxic activity and identification of phytotoxic substances from Schumannianthus dichotomus

Rob M.M., Hossen K., Iwasaki A., Suenaga K., Kato-Noguchi H.

Plants (Plants) 9 ( 1 ) 2020.01

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. The phytotoxic potential of plants and their constituents against other plants is being increasingly investigated as a possible alternative to synthetic herbicides to control weeds in crop fields. In this study, we explored the phytotoxicity and phytotoxic substances of Schumannianthus dichotomus, a perennial wetland shrub native to Bangladesh, India, and Myanmar. Leaf extracts of S. dichotomus exerted strong phytotoxicity against two dicot species, alfalfa and cress, and two monocot species, barnyard grass and Italian ryegrass. A bioassay-driven purification process yielded two phenolic derivatives, syringic acid and methyl syringate. Both constituents significantly inhibited the growth of cress and Italian ryegrass in a concentration-dependent manner. The concentrations required for 50% growth inhibition (I50 value) of the shoot and root growth of cress were 75.8 and 61.3 μM, respectively, for syringic acid, compared with 43.2 and 31.5 μM, respectively, for methyl syringate. Similarly, to suppress the shoot and root growth of Italian rye grass, a greater amount of syringic acid (I50 = 213.7 and 175.9 μM) was needed than methyl syringate (I50 = 140.4 to 130.8 μM). Methyl syringate showed higher phytotoxic potential than syringic acid, and cress showed higher sensitivity to both substances. This study is the first to report on the phytotoxic potential of S. dichotomus and to identify phytotoxic substances from this plant material.

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Allelopathic potential and identification of two allelopathic substances in Eleocharis atropurpurea

Zaman F., Iwasaki A., Suenaga K., Kato-Noguchi H.

Plant Biosystems (Plant Biosystems) 2020

ISSN 11263504

© 2020, © 2020 Societá Botanica Italiana. Eleocharis atropurpurea is an annual weed and distributed widely in pantropical and subtropical regions. Yet, there have been no studies on the allelopathy of E. atropurpurea. Therefore, we investigated the allelopathic potential of E. atropurpurea to identify allelopathic substances from it. The aqueous methanolic extracts of E. atropurpurea showed an inhibitory effect on the seedling growth of lettuce, rapeseed, barnyard grass and foxtail fescue. Inhibition was species- and concentration-dependent. Two substances, syringaldehyde and acetosyringone, were isolated by using chromatography and using spectroscopy their structures were determined. Syringaldehyde and acetosyringone inhibited the shoot and root growth of cress and barnyard grass at concentrations greater than 3.0 mM except shoot growth of barnyard grass by acetosyringone. Concentration and seedling growth of cress and barnyard grass displayed a negative correlation. The I50 values of syringaldehyde and acetosyringone for the shoot and root growth of cress were 1.67 and 1.61 mM, and 1.49, and 1.29 mM, respectively, whereas for the shoot and root growth of barnyard grass the values were 4.09 and 2.41 mM, and 4.54 and 1.92 mM, respectively. Therefore, it is suggested that these compounds may contribute to the inhibitory effects of E. atropurpurea.

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Potential use of Schumannianthus dichotomus waste: the phytotoxic activity of the waste and its identified compounds

Rob M.M., Iwasaki A., Suenaga K., Ozaki K., Teruya T., Kato-Noguchi H.

Journal of Environmental Science and Health - Part B Pesticides, Food Contaminants, and Agricultural Wastes (Journal of Environmental Science and Health - Part B Pesticides, Food Contaminants, and Agricultural Wastes) 2020

ISSN 03601234

© 2020 Taylor & Francis Group, LLC. The phytotoxic potential of the leaves and twigs of Schumannianthus dichotomus, discarded in the mat-making industry against four test plants (lettuce (Lactuca sativa L.), rapeseed (Brassica napus L.), foxtail fescue (Vulpia myuros (L.) C.C. Gmel.) and timothy (Phleum pratense L.)) was investigated and found strong phytotoxic activity. An assay-guided fractionation of S. dichotomus extarcts against cress (Lepidium sativum L.) through a series of column chromatography steps yielded two compounds, 8-(5-oxo-2,5-dihydrofuran-2-yl) octanoic acid (ODFO) and (E)-6-hydroxy-2,6-dimethylocta-2,7-dienoic acid (8-carboxylinalool). ODFO and 8-carboxylinalool showed strong phytotoxic activity against cress and timothy. The concentrations required for 50% growth inhibition (I 50 value) of the seedlings of cress and timothy were 111.94–128.01 and 36.30–91.75 µM, respectively, for ODFO, but the values were much higher at 315.98–379.13 and 107.92–148.41 µM, respectively, for 8-carboxylinalool, indicating the stronger phytotoxic activity of ODFO. This study is the first to isolate ODFO and 8-carboxylinalool from S. dichotomus and their phytotoxic potential while ODFO is firstly encountered from any natural source. The growth inhibitory activity of the identified compounds may explain their role in the phytotoxic activity of S. dichotomus, which suggests the possible use of its leaves and twigs or its active constituents as natural bioherbicides.

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Assessment of allelopathic potential of Dalbergia cochinchinensis Pierre and its growth inhibitory substance

Krumsri R., Iwasaki A., Suenaga K., Kato-Noguchi H.

Emirates Journal of Food and Agriculture (Emirates Journal of Food and Agriculture) 32 ( 7 ) 513 - 521 2020

ISSN 2079052X

In forestry systems, many types of forest trees possess allelopathic properties and release a wide variety of allelochemicals that influence the growth and development of surrounding species. Dalbergia cochinchinensis, a forest tree distributed in Southeast Asia, is reputed to possess several biological properties and contain several secondary compounds. However, there have been no studies on the allelopathy of D. cochinchinensis. Therefore, D. cochinchinensis leaf extracts were examined for allelopathic potential. The present study showed that D. cochinchinensis extracts significantly inhibited the seedling growth of six test plant species: timothy, Italian ryegrass, barnyard grass, cress, alfalfa, and lettuce. Concentrations of the D. cochinchinensis extracts negatively correlated with the shoot length (r = −0.50 to −0.89) and root length (r = −0.65 to −0.89) of all the test plant species. The extracts were then purified using several chromatographic steps and the growth inhibitory substance was isolated. The chemical structure of the substance was identified through spectroscopic analysis as 3,4-dihydroxybenzoic acid (protocatechuic acid). Protocatechuic acid at a concentration higher than 3 mM significantly inhibited the growth of cress seedlings, whereas barnyard grass seedlings were inhibited at concentrations higher than 0.3 mM. As the protocatechuic acid concentration increased, the seedling growth of cress and barnyard grass was significantly reduced. I50 values showed the effectiveness of protocatechuic acid against both test plant species was apparently greater on root growth than shoot growth. Results of this study suggest that protocatechuic acid isolated from D. cochinchinensis might be responsible for its inhibitory effects.

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Garcienone, a novel compound involved in allelopathic activity of Garcinia Xanthochymus hook

Rob M.M., Iwasaki A., Suzuki R., Suenaga K., Kato-Noguchi H.

Plants (Plants) 8 ( 9 ) 2019.09

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Plants are sources of diversified allelopathic substances that can be investigated for use in eco-friendly and efficient herbicides. An aqueous methanol extract from the leaves of Garcinia xanthochymus exhibited strong inhibitory activity against barnyard grass (Echinochloa crus-galli (L.) P. Beauv.), foxtail fescue (Vulpia myuros (L.) C.C.), alfalfa (Medicago sativa L.), and cress (Lepidium sativum L.), and appears to be a promising source of allelopathic substances. Hence, bio-activity guided purification of the extract through a series of column chromatography steps yielded a novel compound assigned as garcienone ((R, E)-5-hydroxy-5-((6S, 9S)-6-methyl-9-(prop-13-en-10-yl) tetrahydrofuran-6-yl) pent-3-en-2-one). Garcienone significantly inhibited the growth of cress at a concentration of 10 µM. The concentrations resulting in 50% growth inhibition (I50) of cress roots and shoots were 120.5 and 156.3 µM, respectively. This report is the first to isolate and identify garcienone and to determine its allelopathic potential.

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Marine natural products: A source of novel anticancer drugs

Khalifa S., Elias N., Farag M., Chen L., Saeed A., Hegazy M., Moustafa M., El-Wahed A., Al-Mousawi S., Musharraf S., Chang F., Iwasaki A., Suenaga K., Alajlani M., Göransson U., El-Seedi H.

Marine Drugs (Marine Drugs) 17 ( 9 ) 2019.08

© 2019 by the authors. Cancer remains one of the most lethal diseases worldwide. There is an urgent need for new drugs with novel modes of action and thus considerable research has been conducted for new anticancer drugs from natural sources, especially plants, microbes and marine organisms. Marine populations represent reservoirs of novel bioactive metabolites with diverse groups of chemical structures. This review highlights the impact of marine organisms, with particular emphasis on marine plants, algae, bacteria, actinomycetes, fungi, sponges and soft corals. Anti-cancer effects of marine natural products in in vitro and in vivo studies were first introduced; their activity in the prevention of tumor formation and the related compound-induced apoptosis and cytotoxicities were tackled. The possible molecular mechanisms behind the biological effects are also presented. The review highlights the diversity of marine organisms, novel chemical structures, and chemical property space. Finally, therapeutic strategies and the present use of marine-derived components, its future direction and limitations are discussed.

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Total Synthesis, Stereochemical Revision, and Biological Assessment of Iriomoteolide-2a

Sakamoto K., Hakamata A., Iwasaki A., Suenaga K., Tsuda M., Fuwa H.

Chemistry - A European Journal (Chemistry - A European Journal) 25 ( 36 ) 8528 - 8542 2019.06

ISSN 09476539

© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Iriomoteolide-2a is a marine macrolide metabolite isolated from a cultured broth of the benthic dinoflagellate Amphidinium sp. HYA024 strain. This naturally occurring substance was reported to show remarkable cytotoxic activity against human cancer cell lines HeLa and DG-75 and in vivo antitumor activity against murine leukemia P388 cell line. Herein, the total synthesis, stereochemical revision, and biological assessment of iriomoteolide-2a are reported in detail. Total synthesis of the proposed structure 1 of iriomoteolide-2a featured a late-stage convergent assembly of three components by a Suzuki–Miyaura coupling, an esterification, and a ring-closing metathesis. However, the NMR data of synthetic 1 were not identical to those of the natural product. Careful analysis of the NMR data of the authentic material and synthesis/NMR analysis of appropriately designed model compounds led to consideration of four possible stereoisomers 2–5 as candidates for the correct structure. Accordingly, total syntheses of 2–5 were achieved by taking advantage of the convergent strategy, and comparison of the NMR spectra of synthetic 2–5 with those of the natural product led to the conclusion that 5 shows the correct relative configuration of iriomoteolide-2a. The absolute configuration of this natural product was finally established through chiral HPLC analysis of synthetic 5/ent-5 with the authentic sample. The antiproliferative activity of the synthetic compounds was assessed against HeLa and A549 cells to show that, in contrast to expectation, synthetic 5 and ent-5 were only marginally active in these cell lines. This work clearly underscores the vital role of total synthesis in the establishment of the structure and biological activity of natural products.

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Kyanamide, a new Ahp-containing depsipeptide from marine cyanobacterium Caldora penicillata

Ozaki K., Iwasaki A., Suenaga K., Teruya T.

Tetrahedron (Tetrahedron) 75 ( 25 ) 3382 - 3386 2019.06

ISSN 00404020

© 2019 Elsevier Ltd Kyanamide (1), a new depsipeptide containing 3-amino-6-hydroxy-2-piperidone moiety, was isolated from the Caldora penicillata marine cyanobacterium collected in Okinawa. Its structure was determined by spectroscopic analysis and Marfey's analysis of acid hydrolysate. Kyanamide exhibited moderate cytotoxicity against HeLa S3 cells. 1 also exhibited potent protease inhibitory activity against elastase and chymotrypsin with IC50 values of 0.13 nM and 1.1 μM.

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Phytotoxic potential of Chrysopogon aciculatus (Retz.) Trin. (Poaceae)

Islam M., Zaman F., Iwasaki A., Suenaga K., Kato-Noguchi H.

Weed Biology and Management (Weed Biology and Management) 19 ( 2 ) 51 - 58 2019.06

ISSN 14446162

© 2019 Weed Science Society of Japan The creeping weed, Chrysopogon aciculatus (Retz.) Trin., is widely known for its use as folk medicine, while its phytotoxic potential has not been examined. Therefore, we carried out an investigation into the phytotoxic potential of C. aciculatus to identify phytotoxic substances. C. aciculatus extracts showed inhibitory effects on shoot and root growth of cress, lettuce, rapeseed, and Italian ryegrass. Inhibition was both species-dependent and concentration-dependent. Two substances, (9S,10E,12Z)-9-hydroxyoctadeca-10,12-dienoic acid (9-HO-ODDEA) and rhizopycnin A, were isolated using chromatographies and characterized by spectral analysis. 9-HO-ODDEA retarded shoot and root growth of cress at concentrations higher than 1.0 and 0.3 mM, respectively, while on cress seedling by rhizopycnin A, the inhibition began from 1.0 mM. The concentrations needed for 50% inhibition of the shoot and root growth of test plants ranged from 1.71–2.31, and 0.71–0.72 mM for 9-HO-ODDEA and rhizopycnin A, respectively. These results indicate that these substances may contribute, to a certain extent, to the phytotoxic activity of C. aciculatus.

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Phytotoxic activity of kiwifruit leaves and isolation of a phytotoxic substance

Okada S., Iwasaki A., Kataoka I., Suenaga K., Kato-Noguchi H.

Scientia Horticulturae (Scientia Horticulturae) 250 243 - 248 2019.05

ISSN 03044238

© 2019 Elsevier B.V. When aged kiwifruit (Actinidia deliciosa (A. Chev.) C.F. Liang et A.R. Ferguson) plants are replaced with young ones, the growth and productivity of the young plants were occasionally lower than expected. This symptom is typical of the replant problems reported in several fruit trees. Phytotoxic substances released from the plant are assumed to be involved in the replant problems. Although some substances contained in kiwifruit leaves have been reported to have phytotoxic activity, little is known about phytotoxicity and phytotoxic substances in kiwifruit leaves on the growth of the kiwifruit itself. Therefore, this study determined the phytotoxic activity of kiwifruit leaf extracts and soil extracts and identified a phytotoxic substance in kiwifruit leaves. Extracts of kiwifruit leaves inhibited the growth of Lepidium sativum, Lactuca sativa, Medicago sativa, Phleum pratense, Lolium multiflorum, Echinochloa crus-galli, and kiwifruit seedlings. The soil extracts also inhibited the growth of L. sativum. These results suggest that kiwifruit leaf extracts and soil extracts may possess phytotoxic substances. (-)-Epicatechin was isolated from the extracts with bioassay-guided separations using chromatography. The concentrations of (-)-epicatechin required for 50% growth inhibition of the hypocotyls and radicles of L. sativum were 27.9 and 10.7 mM, respectively, and those for the hypocotyls and radicles of kiwifruit were 13.9 and 7.6 mM, respectively. This substance may contribute to the phytotoxic activity of kiwifruit leaf extracts and may be involved in the kiwifruit replant problem.

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(+)-Isoamericanol A: A Plant Growth Inhibitor from Heliotropium indicum

Chaipon S., Boonmee S., Iwasaki A., Suenaga K., Kato-Noguchi H.

Natural Product Communications (Natural Product Communications) 14 ( 5 ) 2019.05

ISSN 1934578X

© The Author(s) 2019 Article reuse guidelines: sagepub.com/journals-permissions A plant growth inhibitory substance was isolated from Heliotropium indicum by bioassay-guided purification and characterized to be (+)-isoamericanol A. (+)-Isoamericanol A significantly inhibited seedling growth of cress at a concentration greater than 0.1 mM. The concentrations of (+)-isoamericanol A required for 50% growth inhibition of cress roots and hypocotyls were 0.5 and 0.4 mM, respectively. This inhibition indicates that (+)-isoamericanol A had a growth inhibitory activity and may contribute to the allelopathic effect of H. indicum. This report is the first on the plant growth inhibitory activity of (+)-isoamericanol A as an allelopathic substance.

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Allelopathic Potency and an Active Substance from Anredera cordifolia (Tenore) Steenis

Bari I., Kato-Noguchi H., Iwasaki A., Suenaga K.

Plants (Plants) 8 ( 5 ) 2019.05

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Anredera cordifolia (Tenore) Steenis is widely planted as an ornamental and medicinal plant in Indonesia. On the other hand, in some other countries this plant is classified as a noxious weed. As a harmful weed, A. cordifolia is reported to have the ability to smother all native vegetation, collapse canopies of tall trees, cultivate as a ground cover and disrupt native seedling development. There is no available information about the involvement of any allelochemicals from A. cordifolia related to these issues. The present study evaluated the allelopathic effect by isolating and identifying the allelopathic substance from A. cordifolia leaf extract. The allelopathic potency of A. cordifolia was determined by a series of bioassays of shoot and root growth on some selected test plants. Separation and purification of the active substances was achieved through several chromatography processes. Finally, the substances with allelopathic activity were identified through high-resolution electrospray ionization mass spectrometry (HRESIMS) analysis and determined by the specific rotation of compound, proton and carbon NMR spectroscopies. The results show that A. cordifolia possesses allelopathic properties which affect other plant species. The isolated compound from the plant material, 3-hydroxy-alpha-ionone, may contribute to the allelopathic effects of A. cordifolia.

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Phytotoxic property of Piper retrofractum fruit extracts and compounds against the germination and seedling growth of weeds

Suwitchayanon P., Ohno O., Suenaga K., Kato-Noguchi H.

Acta Physiologiae Plantarum (Acta Physiologiae Plantarum) 41 ( 3 ) 2019.03

ISSN 01375881

© 2019, Franciszek Górski Institute of Plant Physiology, Polish Academy of Sciences, Kraków. The fruits of Piper retrofractum Vahl. contain a variety of compounds, but no phytotoxic compound with plant growth inhibitory activity has been reported. Therefore, the phytotoxic activity of P. retrofractum fruit extracts was investigated and found the reduction of seedling growth of cress, lettuce, alfalfa, barnyard grass, Italian ryegrass, and jungle rice. Seven bioactive compounds were isolated from the fruit extracts and identified as 3-phenylpropanoic acid (1), (2E,4E)-methyl piperate (2), (2E,4Z)-methyl piperate (3), piperlonguminine (4), dihydropiperine (5), isochavicine (6), and piperine (7). There have been no reports for their phytotoxic activity. The activity of these compounds was determined against the germination and seedling growth of cress and barnyard grass. The total germination percentage (GP) of cress was significantly inhibited by 1, 2, and 6 (40–100% inhibition), while its germination index or progressive total of cumulative germination (GI) was the most sensitive to 1, leading to the longest time required for 50% germination (T50) at 57 h behind control. However, the seedling growth of cress was highly inhibited by 6 with I50 values of 11 µM. The compounds 1 and 5–7 showed significant inhibition on GP of barnyard grass by 55–47%, while 5 and 1 effectively reduced GI and extended T50 to 42–48 h behind control, and 7 showed the most growth inhibition with I50 values of 37 µM. The inhibitory effects of the seven compounds indicate the phytotoxic property of P. retrofractum fruits, which 1, 5–7 may be the main compounds responsible for the phytotoxicity.

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Phytotoxic activity of Chinese violet (Asystasia gangetica (L.) T. Anderson) and two phytotoxic substances

Suzuki M., Chozin M., Iwasaki A., Suenaga K., Kato-Noguchi H.

Weed Biology and Management (Weed Biology and Management) 19 ( 1 ) 3 - 8 2019.03

ISSN 14446162

© 2019 Weed Science Society of Japan Chinese violet (Asystasia gangetica (L.) T. Anderson) is a perennial invasive weed belonging to Acanthaceae. Leaves of this weed have been suggested to possess phytotoxic activity. However, phytotoxic substances in this weed have not yet been reported. Therefore, the present study investigated phytotoxic activity of Chinese violet extracts and phytotoxic substances. The extracts of Chinese violet leaves inhibited the root and shoot growth of cress, lettuce, alfalfa, barnyard grass, ryegrass, and timothy, where the level of inhibition increased with increasing extract concentrations. Bioassay-guided separations of the extracts led to isolation of two phytotoxic substances, indole-3-carboxaldehyde and (6R,9S)-3-oxo-α-ionol. Indole-3-carboxaldehyde significantly inhibited the root and shoot growth of cress at concentrations ≥100 and 30 μmol L −1 , respectively, and concentrations of the substance required for 50% growth inhibition were 210 and 127 μmol L −1 for cress roots and shoots, respectively. The other substance, (6R,9S)-3-oxo-α-ionol, was reported to have strongly inhibited cress roots and shoots. The present results suggest that Chinese violet contains two phytotoxic substances indole-3-carboxaldehyde and (6R,9S)-3-oxo-α-ionol, and those substances may play an important role in the phytotoxic activity of Chinese violet.

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Evaluation of allelopathic competency of Lamium amplexicaule and identification of its allelopathic active substance

Sakamoto C., Suzuki M., Iwasaki A., Suenaga K., Kato-Noguchi H.

Emirates Journal of Food and Agriculture (Emirates Journal of Food and Agriculture) 31 ( 2 ) 76 - 80 2019.02

ISSN 2079052X

© 2017 United Arab Emirates University. The weedy annual grass Lamium amplexicaule (L.) originated from the Mediterranean region, spreads quickly, and becomes naturalized in areas it invades. It was assumed that volatile phytotoxic substances are one of the invasive characteristics of L. amplexicaule. However, no volatile compound has been found. Therefore, we re-evaluated the allelopathic potential of L. amplexicaule and investigated the phytotoxic substances with allelopathic activity. An extract of L. amplexicaule inhibited the root and shoot growth of Lepidium sativum, Lactuca sativa, Arctium lappa, Lolium multiflorum Lam., Echinochloa crus-galli, and Vulpia myuros, which indicates that the extract has an allelopathic effect. The extract was purified using bioassay-guided chromatographic separations, and a phytotoxic substance with allelopathic activity was isolated and characterized as methyl caffeate. The compound significantly inhibited the root and shoot growth of L. sativum and L. multiflorum. The present results suggest that methyl caffeate may contribute to the allelopathic effect of the L. amplexicaule extracts and consequently, may be partly responsible for the invasive characteristics of the species.

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Minnamide A, a Linear Lipopeptide from the Marine Cyanobacterium Okeania hirsuta

Sumimoto S., Kobayashi M., Sato R., Shinomiya S., Iwasaki A., Suda S., Teruya T., Inuzuka T., Ohno O., Suenaga K.

Organic Letters (Organic Letters) 2019

Research paper (scientific journal), Accepted, ISSN 15237060

© 2019 American Chemical Society. Minnamide A is a lipopeptide with a unique repeating structure consisting of hydroxy and proposed β-branched methyl groups. The absolute configuration of minnamide A was determined by a combination of chemical degradation, chiral HPLC analyses, and synthetic methods. Minnamide A showed growth-inhibitory activity toward HeLa cells with an IC 50 value of 0.17 μM and rapidly induced cell death at a concentration of 2 μM. Minnamide A induced the copper-mediated accumulation of reactive oxygen species.

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Evaluation of phytotoxic potential and identification of phytotoxic substances in Cassia alata Linn. leaves

Das K., Iwasaki A., Suenaga K., Kato-Noguchi H.

Acta Agriculturae Scandinavica Section B: Soil and Plant Science (Acta Agriculturae Scandinavica Section B: Soil and Plant Science) 2019

ISSN 09064710

© 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group. Cassia alata (Caesalpiniaceae) is a large perennial shrub native to tropical America. It is an important medicinal and ornamental plant and has been reported to possess several pharmacological properties. However, phytotoxic substances from C. alata have not yet been documented in the literature. Therefore, this study seeks to evaluate the phytotoxic potential of C. alata leaves and to identify inhibitory substances for the purpose of eco-friendly weed management. The effect of aqueous methanol extracts of C. alata on the seedling growth of alfalfa, cress, lettuce, rapeseed, barnyard grass, foxtail fescue, Italian ryegrass, and timothy was examined. The level of inhibition of the extracts corresponded to concentration. Several chromatographic steps were performed to separate the extracts, and through spectroscopic analysis, two active substances were isolated and characterised as rutin and syringone. These two active substances significantly inhibited the seedling growth of cress and foxtail fescue. The range of I 50 values (required concentration for 50% growth inhibition) of rutin and syringone for the seedling growth of cress and foxtail fescue were 129.5–417.8 and 160.1–466.5 µM, respectively. These results indicate that the two identified active phytotoxic substances from C. alata may be responsible for its growth inhibitory properties.

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Plant growth inhibitory activity of the extracts of acmella oleracea and its growth inhibitory substances

Kato-Noguchi H., Suwitchayanon P., Boonmee S., Iwasaki A., Suenaga K.

Natural Product Communications (Natural Product Communications) 14 ( 6 ) 2019

ISSN 1934578X

© The Author(s) 2019 Aqueous methanol extracts of Acmella oleracea inhibited the growth of roots and shoots of cress (Lepidum sativum), lettuce (Lactuca sativa), Italian ryegrass (Lolium multiflorum), and barnyard grass (Echinochloa crus-galli) with the extract concentration-dependent manner. The extracts were then purified and 2 growth inhibitory substances were isolated and identified by spectral data as (E,E)-2,4-undecadien-8,10-diynoic acid isobutylamide (compound 1) and nona-(2Z)-en-6,8-diynoic acid 2-phenylethylamide (compound 2). Compound 1 inhibited the growth of cress roots and shoots at concentrations greater than 0.3 mM and that of barnyard grass root at concentrations greater than 0.03 mM. Compound 2 inhibited the growth of cress shoots and barnyard grass roots at concentrations greater than 1 mM. The inhibition on the seedling growth indicates that both compounds had growth inhibitory activity and may contribute to the inhibitory effect of A. oleracea extracts. This is the first report of having growth inhibitory activity of compounds 1 and 2 on plants.

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Phytotoxic activity of crop residues from Burdock and an active substance

Suzuki M., Iwasaki A., Suenaga K., Kato-Noguchi H.

ISSN 03601234

© 2019, © 2019 Taylor & Francis Group, LLC. Problems related to weed management such as outbreaks of herbicide-resistant weeds have recently increased. An interesting approach to such problems is to use plant materials with phytotoxic activity. Burdock (Arctium lappa L.) is a biennial herb belonging to Asteraceae and is cultivated in several countries. The present study investigated the phytotoxic activity of burdock and its active substances. Extracts of both burdock leaves and roots inhibited the shoot and root growth of cress and barnyard grass, where the level of inhibition increased with increasing extract concentration. The leaf extracts had 2.0–2.5 times higher activity than the root extracts. Bioassay-guided separations of the leaf extracts led to isolation of a phytotoxic substance, onopordopicrin. Onopordopicrin significantly inhibited the shoot and root growth of cress and barnyard grass. The concentrations of the substance required for 50% growth inhibition were 0.27 and 0.26 mM for cress shoots and roots, respectively, and 1.86 and 0.35 mM for barnyard grass shoots and roots, respectively. The present results suggest that burdock leaves have high phytotoxic activity and onopordopicrin may play a major role in the activity. Burdock leaves may be a good resource for weed management.

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Isolation and Total Synthesis of Mabuniamide, a Lipopeptide from an Okeania sp. Marine Cyanobacterium

Ozaki K., Iwasaki A., Sezawa D., Fujimura H., Nozaki T., Saito-Nakano Y., Suenaga K., Teruya T.

Journal of Natural Products (Journal of Natural Products) 82 ( 10 ) 2907 - 2915 2019

ISSN 01633864

Copyright © 2019 American Chemical Society and American Society of Pharmacognosy. The bioassay-guided fractionation of an Okeania sp. marine cyanobacterium collected in Okinawa led to the isolation of the lipopeptide mabuniamide (1). The gross structure of 1 was determined by spectroscopic analyses, and its absolute configuration was determined using Marfey's analysis of the acid hydrolysate of 1. The absolute configuration of 1 was confirmed by total synthesis. Mabuniamide (1) stimulated glucose uptake in cultured rat L6 myotubes. In addition, mabuniamide (1) and its stereoisomer (2) exhibited moderate antimalarial activity.

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Allelopathic property and an allelopathic substance in Eleocharis atropurpurea (Retz.)

Zaman F., Iwasaki A., Suenaga K., Kato-Noguchi H.

Theoretical and Experimental Plant Physiology (Theoretical and Experimental Plant Physiology) 30 ( 4 ) 347 - 355 2018.12

© 2018, Brazilian Society of Plant Physiology. Plants, which include crops, weeds, and trees, are able to release effective allelochemicals that inhibit the growth and development of other plants. Eleocharis atropurpurea, a small, annual tufted weed, is renowned for being widely found in crop fields, yet there have been no studies on the allelopathy of E. atropurpurea (Cyperaceae). Thus, we explored the allelopathic potential and allelochemicals in E. atropurpurea and found that aqueous methanol extracts of E. atropurpurea inhibited the seedling growth of Lepidium sativum, Medicago sativa, Lolium multiflorum, and Phleum pratense. There was a significant negative correlation between the seedling growth of the test plants and extract concentration. Extracts were purified using several chromatographic steps and one growth inhibitory substance was isolated and identified by spectroscopic analysis as trans-ferulaldehyde. The active substance trans-ferulaldehyde significantly inhibited the shoot and root length of Lepidium sativum at concentrations higher than 1.0 and 3.0 mM, respectively, whereas the seedling length of Echinochloa crus-galli was inhibited by trans-ferulaldehyde at concentrations higher than 3.0 mM. The trans-ferulaldehyde I50 values for the growth of Lepidium sativum and Echinochloa crus-galli were in the range of 0.73–3.68 mM. The growth inhibitory results of this study suggest that trans-ferulaldehyde may be responsible for the inhibitory effects of E. atropurpurea and may contribute to weed allelopathy.

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Hoshinoamides A and B, Acyclic Lipopeptides from the Marine Cyanobacterium Caldora penicillata

Iwasaki A., Tadenuma T., Sumimoto S., Shiota I., Matsubara T., Saito-Nakano Y., Nozaki T., Sato T., Suenaga K.

Journal of Natural Products (Journal of Natural Products) 81 ( 11 ) 2545 - 2552 2018.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 01633864

Copyright © 2018 American Chemical Society and American Society of Pharmacognosy. Hoshinoamides A (1) and B (2), new acyclic lipopeptides, were isolated from the marine cyanobacterium Caldora penicillata. Their structures were elucidated by spectroscopic analyses and degradation reactions. Hoshinoamides A (1) and B (2) did not exhibit any cytotoxicity against HeLa cells at 10 μM, but inhibited the in vitro growth of the malarial parasite Plasmodium falciparum (IC50 = 0.52 and 1.0 μM, respectively).

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Isolation and identification of a phytotoxic substance in kiwifruit leaves

Okada S., Iwasaki A., Kataoka I., Suenaga K., Kato-Noguchi H.

Acta Horticulturae (Acta Horticulturae) 1218 207 - 212 2018.10

© International Society for Horticultural Science. All rights reserved. The yield of kiwifruit [Actinidia deliciosa (A. Chev.) C.F. Liang et A.R. Ferguson] often decreases after 20 years of cultivation. Replanted young kiwifruit plants cannot grow well in fields where aged trees were previously cultivated. Phytotoxicity is considered one possible reason for this problem. However, allelopathic or phytotoxic substances from kiwifruit have not been reported. This study aimed to isolate and identify potentially allelopathic active substances in kiwifruit leaves. Extracts from kiwifruit leaves inhibited the growth of cress, suggesting that kiwifruit leaf extracts may contain growth-inhibitory substances. The extracts were then purified using a silica-gel column, Sephadex LH-20 column, ODS cartridge, and HPLC. The inhibitory activity of all fractions obtained in each purification step was determined by the cress bioassay. Quercitrin was finally isolated and identified as a growth-inhibitory substance. This substance inhibited cress root growth by more than 50% of control at 3 mM. The aglycone of quercitrin, quercetin, did not significantly inhibit cress growth. Quercitrin may work as an allelopathic substance and cause the kiwifruit replant problem. Further study is in progress to investigate the influence of kiwifruit leaf extracts and these flavonoids on kiwifruit seedlings.

Croissamide, a proline-rich cyclic peptide with an N-prenylated tryptophan from a marine cyanobacterium Symploca sp.

Iwasaki K., Iwasaki A., Sumimoto S., Sano T., Hitomi Y., Ohno O., Suenaga K.

Tetrahedron Letters (Tetrahedron Letters) 59 ( 42 ) 3806 - 3809 2018.10

Research paper (scientific journal), Accepted, ISSN 00404039

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Unified Total Synthesis, Stereostructural Elucidation, and Biological Evaluation of Sarcophytonolides

Takamura, Hiroyoshi, Kikuchi, Takahiro, Iwamoto, Kohei, Nakao, Eiji, Harada, Naoki, Otsu, Taichi, Endo, Noriyuki, Fukuda, Yuji, Ohno, Osamu, Suenaga, Kiyotake, Guo, Yue-Wei, Kadota, Isao

Journal of Organic Chemistry 83 ( 18 ) 11028 - 11056 2018.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 0022-3263

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Isolation of Jahanene and Jahanane, and Total Synthesis of the Jahanyne Family

Iwasaki, Arihiro, Fujimura, Haruka, Okamoto, Shinichiro, Kudo, Takafumi, Hoshina, Shizuka, Sumimoto, Shimpei, Teruya, Toshiaki, Suenaga, Kiyotake

Journal of Organic Chemistry 83 ( 17 ) 9592 - 9603 2018.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 0022-3263

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ISOLATION AND IDENTIFICATION OF A GROWTH INHIBITORY SUBSTANCE FROM HELIOTROPIUM INDICUM L.

Chaipon, Sirinapa, Suwitchayanon, Prapaipit, Iwasaki, Arihiro, Suenaga, Kiyotake, Kato-Noguchi, Hisashi

Acta Biologica Hungarica 69 ( 3 ) 259 - 269 2018.09

Research paper (scientific journal), Accepted, ISSN 0236-5383

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Izenamides A and B, Statine-Containing Depsipeptides, and an Analogue from a Marine Cyanobacterium

Kanamori Yuki, Iwasaki Arihiro, Sumimoto Shimpei, Matsubara Teruhiko, Sato Toshinori, Suenaga Kiyotake

Journal of Natural Products 81 ( 7 ) 1673 - 1681 2018.07

Accepted, ISSN 0163-3864

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Plant growth inhibitory activity and active substances with allelopathic potential of cogongrass (Imperata cylindrica) rhizome

Suzuki Masahiko, Tominaga Tohru, Ohno Osamu, Iwasaki Arihiro, Suenaga Kiyotake, Kato-Noguchi Hisashi

Weed Biology and Management 8 ( 2 ) 92 - 98 2018.06

Accepted, ISSN 1444-6162

Cogongrass (Imperata cylindrica [L.] Raeusch.) is a perennial rhizomatous grass that belongs to the Poaceae and is widely distributed in tropical, subtropical and temperate regions over the world. The grass is strongly invasive and is suggested to have allelopathic potential. However, limited information is available on allelopathic substances in cogongrass rhizomes. Therefore, the allelopathic potential and substances in cogongrass rhizomes were investigated. The extracts of cogongrass rhizomes inhibited the root and shoot growth of barnyard grass, ryegrass, timothy, cress, lettuce and alfalfa. After bioassay-guided separations of the extracts, four growth inhibitory substances, 5-methoxyflavone, 5,2'-dimethoxyflavone, methyl caffeate and abscisic acid, were isolated. 5-Methoxyflavone, 5,2'-dimethoxyflavone and methyl caffeate significantly inhibited the root and shoot growth of cress at concentrations of ≥0.03-0.3m mol L^-1 and their concentrations required for 50% growth inhibition were 0.079-0.24, 0.23-1.1 and 0.59-0.88m mol L^-1, respectively. The other isolated substance, abscisic acid, has been reported to have strong growth inhibitory activity. Its concentrations required for 50% growth inhibition on cress were 0.31-0.61μ mol L^-1. The present study suggests that cogongrass rhizomes might have allelopathic potential and that those four substances might contribute to that potential.

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Evaluation of phytotoxic activity of leaf and stem extracts and identification of a phytotoxic substance from Caesalpinia mimosoides Lamk.

Boonmee Sutjaritpan, Iwasaki Arihiro, Suenaga Kiyotake, Kato-Noguchi Hisashi

Theoretical and Experimental Plant Physiology 30 ( 2 ) 129 - 139 2018.06

Accepted

Caesalpinia mimosoides (Fabaceae) has been used as a folk medicine and reported to have pharmacological properties. However, the phytotoxicity of C. mimosoides has not yet been studied. Therefore, the phytotoxic activity of C. mimosoides leaf and stem extracts was evaluated against the growth of dicotyledonous and monocotyledonous plants. Aqueous methanol extracts of C. mimosoides leaves and stems exhibited inhibitory effects on the growth of all the test plants. The growth of the test plants decreased with the increase of concentrations of the extracts. Comparison of the concentrations required for 50% growth inhibition (I₅₀ values) indicates that the leaf extracts had more inhibitory effects than the stem extracts. Thus, the active substances in the leaf extracts were purified using column chromatographic separations and a growth inhibitory substance was isolated and identified as methyl gallate by using spectral analysis. This study reports the first isolation of methyl gallate in C. mimosoides leaves. Methyl gallate at 10 mM completely inhibited the growth of cress shoots and inhibited its roots by 4.7% of control growth. At the same concentration, the shoots and roots of barnyard grass were inhibited by 84.2 and 1.7% of control growth, respectively. I₅₀ values of methyl gallate for the growth of cress and barnyard grass ranged from 2.3 to 2.9 and 0.3 to 30.5 mM, respectively. The results suggest that methyl gallate may be responsible for the phytotoxic effects of C. mimosoides.

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Ypaoamides B and C, Linear Lipopeptides from an Okeania sp. Marine Cyanobacterium

Sueyoshi Kosuke, Yamada Miki, Yamano Aki, Ozaki Kaori, Sumimoto Shimpei, Iwasaki Arihiro, Suenaga Kiyotake, Teruya Toshiaki

Journal of Natural Products 81 ( 4 ) 1103 - 1107 2018.04

Accepted, ISSN 0163-3864

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Total synthesis of janadolide

Ojima Daisuke, Mine Hitomi, Iwasaki Arihiro, Suenaga Kiyotake

Tetrahedron Letters 59 ( 14 ) 1360 - 1362 2018.04

Accepted, ISSN 0040-4039

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Caldorin, a new polyketide from the marine cyanobacterium Caldora penicillata

Shiota Ikuma, Iwasaki Arihiro, Sumimoto Shimpei, Tomoda Hiroshi, Suenaga Kiyotake

Tetrahedron Letters 59 ( 13 ) 1261 - 1263 2018.03

Accepted, ISSN 0040-4039

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Design, synthesis and anti-malarial activities of synthetic analogs of biselyngbyolide B, a Ca2+ pump inhibitor from marine cyanobacteria

Sato E., Morita M., Ogawa H., Iwatsuki M., Hokari R., Ishiyama A., Ōmura S., Iwasaki A., Suenaga K.

Bioorganic and Medicinal Chemistry Letters (Bioorganic and Medicinal Chemistry Letters) 28 ( 3 ) 298 - 301 2018.02

ISSN 0960894X

© 2017 Elsevier Ltd Biselyngbyaside, an 18-membered macrolide glycoside from marine cyanobacteria, and its derivatives are known to be sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) inhibitors. Recently, a SERCA orthologue of the malaria parasite, PfATP6, has attracted attention as a malarial drug target. To provide a novel drug lead, we designed new synthetic analogs of biselyngbyolide B, the aglycone of biselyngbyaside, based on the co-crystal structure of SERCA with biselyngbyolide B, and synthesized them using the established synthetic route for biselyngbyolide B. Their biological activities against malarial parasites were evaluated.

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Design, synthesis and anti-malarial activities of synthetic analogs of biselyngbyolide B, a Ca²⁺ pump inhibitor from marine cyanobacteria

Sato Eisuke, Morita Maho, Ogawa Haruo, Iwatsuki Masato, Hokari Rei, Ishiyama Aki, Omura Satoshi, Iwasaki Arihiro, Suenaga Kiyotake

Bioorganic and Medicinal Chemistry Letters 28 ( 3 ) 298 - 301 2018.01

Accepted, ISSN 0960-894X

Biselyngbyaside, an 18-membered macrolide glycoside from marine cyanobacteria, and its derivatives are known to be sarco/endoplasmic reticulum Ca²⁺ ATPase (SERCA) inhibitors. Recently, a SERCA orthologue of the malaria parasite, PfATP6, has attracted attention as a malarial drug target. To provide a novel drug lead, we designed new synthetic analogs of biselyngbyolide B, the aglycone of biselyngbyaside, based on the co-crystal structure of SERCA with biselyngbyolide B, and synthesized them using the established synthetic route for biselyngbyolide B. Their biological activities against malarial parasites were evaluated.

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Identification of 6,7-dimethoxychromone as a potent allelochemical from jatropha podagrica

Boonmee S., Iwasaki A., Suenaga K., Kato-Noguchi H.

Natural Product Communications (Natural Product Communications) 13 ( 11 ) 1515 - 1518 2018

ISSN 1934578X

© 2018 Natural Product Incorporation. Jatropha podagrica Hook. is cultivated as an ornamental plant and is also used in traditional medicine. The species has various pharmacological properties, but it has not yet been investigated for any potential allelopathic activity and allelopathic substances. In this study, an allelopathic active substance was isolated from an aqueous methanol extract of J. podagrica leaves through chromatography and reverse-phase HPLC. The substance was characterized as 6,7- dimethoxychromone by spectral analysis. 6,7-Dimethoxychromone significantly inhibited the shoots and roots of cress at concentrations greater than 0.3 mM. The concentrations required of 6,7-dimethoxychromone for 50% growth inhibition of cress shoots and roots were 0.95 and 0.83 mM, respectively. The inhibitory activity against the seedling growth of cress indicates that 6,7-dimethoxychromone may contribute to the allelopathic effects and may be responsible for the allelopathic activity in J. podagrica. This report is the first on the allelopathic activity of 6,7-dimethoxychromone as an allelopathic substance from J. podagrica.

Total Synthesis of Kanamienamide and Clarification of Biological Activity

Ojima Daisuke, Iwasaki Arihiro, Suenaga Kiyotake

Journal of Organic Chemistry 82 ( 23 ) 12503 - 12510 2017.12

Accepted, ISSN 0022-3263

The total synthesis of kanamienamide, an enamide with an enol ether and an 11-membered macrolactone of marine origin, was achieved. The synthesis features the construction of an enamide adjacent to an enol ether by Buchwald amidation and an 11-membered ring by Mitsunobu lactonization. In addition, on the basis of the biological assay of synthetic 1, we clarified that kanamienamide (1) was not an apoptosis-like cell death inducer, as reported in the isolation paper, and revealed its real biological activity as a necrosis-like cell death inducer.

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Total Synthesis of Kanamienamide and Clarification of Biological Activity

Ojima Daisuke, Iwasaki Arihiro, Suenaga Kiyotake

Journal of Organic Chemistry 82 ( 23 ) 12503 - 12510 2017.12

Accepted, ISSN 0022-3263

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2-Methoxystypandrone, a potent phytotoxic substance in Rumex maritimus L

Islam Md Shafiqul, Iwasaki Arihiro, Suenaga Kiyotake, Kato-Noguchi Hisashi

Theoretical and Experimental Plant Physiology 29 ( 4 ) 195 - 202 2017.12

Accepted

Herbicide use has raised concerns which results in the need to find an alternative approach, using natural methods, of controlling weeds. Phytotoxic substances released from plants have been used to manage weeds biologically. Rumex maritimus, belonging to the Polygonaceae family, is well known to have a wide range of biological properties. However, the phytotoxic properties of R. maritimus is not well documented. Thus, we conducted an investigation into the phytotoxic potential of R. maritimus and attempted to find out its phytotoxic substances. Leaf, stem and root extracts of R. maritimus exhibited a strong inhibitory effects on root and shoot length of Lactuca sativa L., Medicago sativa L., Lolium multiflorum Lam., Phleum pratense L. With increasing extract concentration, inhibition increased. One substance, 2-methoxystypandrone, was purified after a series of chromatography and characterized by spectral data. 2-Methoxystypandrone reduced the seedling length of Lepidium sativum at concentration ≥ 3 μM. The required 50% growth inhibition concentration of Lepidium sativum seedling for 2-methoxystypandrone was ranged 5.8–11.8 μM. Therefore, it is suggested that the phytotoxic effects of R. maritimus on the test plants may be caused due to the presence of 2-methoxystypandrone.

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Three new malyngamides from the marine cyanobacterium moorea producens

Sueyoshi Kosuke, Yamano Aki, Ozaki Kaori, Sumimoto Shimpei, Iwasaki Arihiro, Suenaga Kiyotake, Teruya Toshiaki

Marine Drugs 15 ( 12 ) 367 (13 pages) 2017.12

ISSN 1660-3397

Three new compounds of the malyngamide series, 6,8-di-O-acetylmalyngamide 2 (1), 6-O-acetylmalyngamide 2 (2), and N-demethyl-isomalyngamide I (3), were isolated from the marine cyanobacterium Moorea producens. Their structures were determined by spectroscopic analysis and chemical derivatization and degradation. These compounds stimulated glucose uptake in cultured L6 myotubes. In particular, 6,8-di-O-acetylmalyngamide 2 (1) showed potent activity and activated adenosine monophosphate-activated protein kinase (AMPK).

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Two allelopathic substances from Paspalum commersonii Lam.

Zaman Farhana, Iwasaki Arihiro, Suenaga Kiyotake, Kato-Noguchi Hisashi

Acta Agriculturae Scandinavica Section B: Soil and Plant Science 68 ( 4 ) 342 - 348 2017.11

Accepted, ISSN 0906-4710

Paspalum commersonii (Poaceae) is a herbaceous perennial weed distributed in the tropics and subtropics regions and grows mainly in the moist, or even flooded soil. It often appears in the rice field as a competitive weed and difficult to manage. Its strong competitive nature indicates possible allelopathic potential of P. commersonii. However, no studies have been found yet on the allelopathic activity of P. commersonii. Thus, we investigated the allelopathic potential of this weed and determined its allelopathic substances. Aqueous methanol extracts of P. commersonii showed concentration-dependent inhibitory activity on the seedling growth of cress, alfalfa, rapeseed, lettuce, barnyard grass, foxtail fescue, Italian ryegrass, and timothy. Two substances were isolated through bioassay-guided fractionation and their structures were determined through spectral data as dehydrovomifoliol and loliolide. Dehydrovomifoliol and loliolide started inhibiting the shoot and root growth of cress at concentrations greater than 3 and 0.03 mM, respectively. The concentrations required for 50% inhibition (I₅₀) of cress shoot and root growth were 3.34 and >3.50 mM for dehydrovomifoliol and 0.04 and 0.05 mM for loliolide, respectively. These results indicate that both substances may affect the inhibitory activity of P. commersonii.

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Involvement of allelopathy in inhibition of understory growth in red pine forests

Kato-Noguchi Hisashi, Kimura Fukiko, Ohno Osamu, Suenaga Kiyotake

Journal of Plant Physiology 218 66 - 73 2017.11

Accepted, ISSN 0176-1617

Japanese red pine (Pinus densiflora Sieb. et Zucc.) forests are characterized by sparse understory vegetation although sunlight intensity on the forest floor is sufficient for undergrowth. The possible involvement of pine allelopathy in the establishment of the sparse understory vegetation was investigated. The soil of the red pine forest floor had growth inhibitory activity on six test plant species including Lolium multiflorum, which was observed at the edge of the forest but not in the forest. Two growth inhibitory substances were isolated from the soil and characterized to be 15-hydroxy-7-oxodehydroabietate and 7-oxodehydroabietic acid. Those compounds are probably formed by degradation process of resin acids. Resin acids are produced by pine and delivered into the soil under the pine trees through balsam and defoliation. Threshold concentrations of 15-hydroxy-7-oxodehydroabietate and 7-oxodehydroabietic acid for the growth inhibition of L. multiflorum were 30 and 10 μM, respectively. The concentrations of 15-hydroxy-7-oxodehydroabietate and 7-oxodehydroabietic acid in the soil were 312 and 397 μM, respectively, which are sufficient concentrations to cause the growth inhibition because of the threshold. These results suggest that those compounds are able to work as allelopathic agents and may prevent from the invasion of herbaceous plants into the forests by inhibiting their growth. Therefore, allelopathy of red pine may be involved in the formation of the sparse understory vegetation.

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Total Synthesis of Biselyngbyaside

Sato Eisuke, Sato Miho, Tanabe Yurika, Nakajima Naoya, Ohkubo Akifumi, Suenaga Kiyotake

Journal of Organic Chemistry 82 ( 13 ) 6770 - 6777 2017.07

Accepted, ISSN 0022-3263

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Myrislignan, a growth inhibitor from the roots of citronella grass

Suwitchayanon Prapaipit, Suenaga Kiyotake, Iwasaki Arihiro, Kato-Noguchi Hisashi

Natural Product Communications 12 ( 7 ) 1077 - 1078 2017.07

Accepted, ISSN 1934-578X

A phytotoxic compound was isolated from the root extracts of Cymbopogon nardus by bioassay-guided purification and characterized to be myrislignan. Myrislignan significantly inhibited seedling growth of cress at a concentration greater than 100 μM (p < 0.05). The concentrations required for 50% growth inhibition of myrislignan on hypocotyl and root growth of cress were 429 μM and 517 μM, respectively. The inhibition on seedling growth indicated that myrislignan had a phytotoxic activity and may contribute to the phytotoxic effect of C. nardus.

Kohamamides A, B, and C, Cyclic Depsipeptides from an Okeania sp. Marine Cyanobacterium

Iwasaki Arihiro, Shiota Ikuma, Sumimoto Shimpei, Matsubara Teruhiko, Sato Toshinori, Suenaga Kiyotake

Journal of Natural Products 80 ( 6 ) 1948 - 1952 2017.06

Accepted, ISSN 0163-3864

Kohamamides A, B, and C (1-3), new cyclic depsipeptides that belong to the kulolide superfamily, were isolated from an Okeania sp. marine cyanobacterium. Their structures were elucidated by spectroscopic analyses and degradation reactions. Kohamamide B (2) exhibited moderate cytotoxicity against HL60 cells. Although many natural products in the kulolide superfamily have been isolated from cyanobacteria collected in various parts of the world, kohamamides 1-3 are the first members to be isolated from the East Asian marine environment. In addition, unlike other members of this superfamily, kohamamides 1-3 contain a Leu residue adjacent to the Pro residue, rather than another lipophilic amino acid.

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Evaluation of phytotoxic potential and identification of phytotoxic compounds in Rumex maritimus

Islam M. S., Iwasaki A., Suenaga K., Kato-Noguchi H.

Plant Biosystems 152 ( 4 ) 804 - 809 2017.06

Accepted, ISSN 1126-3504

Rumex maritimus (Polygonaceae) is an annual herb and is well known for its use in medicinal treatments. Although the pharmacological properties of R. maritimus are well documented, no phytotoxic activity of R. maritimus has yet been found. Therefore, we investigated the phytotoxic potential of R. maritimus to identify phytotoxic compounds. Inhibitory activity was found in aqueous methanol extracts of R. maritimus on the seedling growth of cress, rapeseed, barnyard grass, and foxtail fescue, in which inhibition increased with increasing extract concentration. Two compounds were isolated using chromatography, and using spectroscopy their structure was determined as 5,7-dihydroxyphthalide and altechromone A. 5,7-Dihydroxyphthalide significantly inhibited cress seedling growth by 27.2–43.0% of control seedlings at 3 mM, whereas altechromone A inhibited seedling growth by 65.4–66.3% at 0.01 mM. The concentrations required for 50% inhibition of cress seedling growth were 1.73–2.48 mM for 5,7-dihydroxyphthalide and 0.66–1.41 mM for altechromone A. These results indicate that the compounds 5,7-dihydroxyphthalide and altechromone A may contribute, to a certain extent, to the phytotoxic activity of R. maritimus.

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Phytotoxic property of the invasive plant Tithonia diversifolia and a phytotoxic substance

Suzuki Masahiko, Iwasaki Arihiro, Suenaga Kiyotake, Kato-Noguchi Hisashi

Acta Biologica Hungarica 68 ( 2 ) 187 - 195 2017.06

Accepted, ISSN 0236-5383

Tithonia diversifolia (Hermsl.) A. Gray is a perennial invasive plant and spreads quickly in the invasive areas. The extracts of T. diversifolia were found to be toxic to several crop plant species such as rice, maize, sorghum, lettuce and cowpea, and several putative allelopathic substances were identified. However, there is limited information available for the effects of T. diversifolia on wild plants including weed plant species. We investigated the allelopathic potential of T. diversifolia extracts on weed plants, and searched for phytotoxic substances with allelopathic activity. An aqueous methanol extract of T. diversifolia leaves inhibited the growth of weed plants, Lolium multiftorum Lam., Phleum pretense L., Echinochloa crus-galli (L.) Beauv. The extract was then purified by several chromatographic runs and a phytotoxic substance with allelopathic activity was isolated and identified by spectral analysis as tagitinin C. The substance inhibited the growth of Lolium multiftorum, Phleum pratense and Echinochloa crusgalli at concentrations greater than 0.1-0.3 mM. The present results suggest that T. diversifolia may possess allelopathic potential on weed plants and tagitinin C may be responsible for the allelopathic effects of T. diversifolia. The allelopathic potential of T. diversifolia may contribute to its invasive characteristics.

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Asparagus decline: Autotoxicity and autotoxic compounds in asparagus rhizomes.

Kato-Noguchi Hisashi, Nakamura Keisuke, Ohno Osamu, Suenaga Kiyotake, Okuda Nobuyuki

Journal of Plant Physiology 213 23 - 29 2017.06

ISSN 0176-1617

Asparagus (Asparagus officinalis L.) is a perennial vegetable, but its crop productivity and quality decrease gradually. One possible reason for “asparagus decline” is thought to be the autotoxicity of asparagus. However, the autotoxic property of asparagus rhizomes remains unknown. The objective of this study was to determine the potential role of rhizomes in the autotoxicity of asparagus. An aqueous methanol extract of asparagus rhizomes inhibited the growth of asparagus seedlings and six other test plants in a concentration-dependent manners: garden cress (Lepidum sativum L.), lettuce (Lactuca sativa L.), alfalfa (Medicago sativa L.), ryegrass (Lolium multiflorum Lam.), timothy (Phleum pratense L.) and barnyardgrass (Echinochloa crus-galli (L.) Beauv.). These results suggest that asparagus rhizomes contain autotoxic compounds. The extract was purified through several chromatographic steps with monitoring the autotoxic activity, and p-coumaric acid and iso-agatharesinol were isolated. These compounds inhibited the shoot and root growth of asparagus and two other test plants, garden cress and ryegrass, at concentrations higher than 0.1 mM. The concentrations required for 50% inhibition of the root and shoot growth of these test plants ranged from 0.36 to 0.85 mM and 0.41–1.22 mM for p-coumaric acid and iso-agatharesinol, respectively. Therefore, these compounds may contribute to the autotoxicity caused by asparagus rhizomes and may be involved in “asparagus decline”.

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N-Octanoyl tyramine, a phytotoxic compound in the roots of Cymbopogon nardus

Suwitchayanon Prapaipit, Ohno Osamu, Suenaga Kiyotake, Kato-Noguchi Hisashi

Acta Physiologiae Plantarum 39 ( 6 ) 123 (8 pages) 2017.06

Accepted, ISSN 0137-5881

Citronella grass (Cymbopogon nardus) is a perennial herb. Many researchers have studied the exploitation of the active compounds in this plant for medicinal purposes, but there have been no studies on its phytotoxic compounds. Therefore, we investigated the phytotoxic active compounds in the roots of C. nardus. A significant inhibition was observed on the germination of cress (Lepidium sativum L.), lettuce (Lactuca sativa L.), barnyard grass (Echinochloa crus-galli L.), and Italian ryegrass (Lolium multiflorum Lam.) by the aqueous methanol extract of C. nardus roots. The extract decreased the total germination percentage (GP) and germination index (GI, progressive total of daily cumulative germination), and extended the time required for 50% germination (T₅₀) of all test species. A phytotoxic compound of the extract was isolated and identified as N-octanoyl tyramine by spectral analysis. This compound showed the inhibition on the germination of cress and barnyard grass. The decline in GP, GI, and T₅₀ was observed at concentrations of 30–2000 μM of N-octanoyl tyramine. The compound also showed the significant inhibition on the growth of cress and barnyard grass seedlings at concentrations greater than 100 and 300 μM, respectively. This study suggests that C. nardus could produce phytotoxic compounds, and N-octanoyl tyramine may be responsible for its phytotoxic activity.

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Apoptosis-inducing activity and antiproliferative effect of Paeoniflorigenone from moutan cortex

Huang Ying, Ohno Osamu, Suenaga Kiyotake, Miyamoto Kenji

Bioscience, Biotechnology and Biochemistry 81 ( 6 ) 1106 - 1113 2017.06

Accepted, ISSN 0916-8451

Ninety samples from the extracts of plants from traditional Chinese medicines were screened for antitumor activity. Paeoniflorigenone (PFG) was isolated as an active ingredient from the root of moutan cortex, which showed the strongest activity. In addition, our data indicated that PFG was cytotoxic and induced apoptosis selectively in the cancer cell lines. These effects were cancelled by the addition of caspase inhibitor Z-VAD-FMK, suggesting that it was mediated by caspase-3 activation.

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Leptolyngbyolides, Cytotoxic Macrolides from the Marine Cyanobacterium Leptolyngbya sp.: Isolation, Biological Activity, and Catalytic Asymmetric Total Synthesis

Cui, Jin, Morita, Maho, Ohno, Osamu, Kimura, Tomoyuki, Teruya, Toshiaki, Watanabe, Takumi, Suenaga, Kiyotake, Shibasaki, Masakatsu

CHEMISTRY-A EUROPEAN JOURNAL 23 ( 35 ) 8500 - 8509 2017.06

Research paper (scientific journal), Joint Work, ISSN 0947-6539

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Biseokeaniamides A, B, and C, Sterol O-Acyltransferase Inhibitors from an Okeania sp. Marine Cyanobacterium

Iwasaki Arihiro, Tadenuma Takato, Sumimoto Shimpei, Ohshiro Taichi, Ozaki Kaori, Kobayashi Keisuke, Teruya Toshiaki, Tomoda Hiroshi, Suenaga Kiyotake

Journal of Natural Products 80 ( 4 ) 1161 - 1166 2017.04

Accepted, ISSN 0163-3864

Biseokeaniamides A, B, and C (1-3), structurally novel sterol O-acyltransferase (SOAT) inhibitors, were isolated from an Okeania sp. marine cyanobacterium. Their structures were elucidated by spectroscopic analyses and degradation reactions. Biseokeaniamide B (2) exhibited moderate cytotoxicity against human HeLa cancer cells, and compounds 1-3 inhibited both SOAT1 and SOAT2, not only at an enzyme level but also at a cellular level. Biseokeaniamides (1-3) are the first linear lipopeptides that have been shown to exhibit SOAT-inhibitory activity.

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Odobromoamide, a terminal alkynyl bromide-containing cyclodepsipeptide from the marine cyanobacterium okeania sp.

Sueyoshi Kosuke, Kudo Takafumi, Yamano Aki, Sumimoto Shimpei, Iwasaki Arihiro, Suenaga Kiyotake, Teruya Toshiaki

Bulletin of the Chemical Society of Japan 90 ( 4 ) 436 - 440 2017.04

Joint Work, ISSN 0009-2673

The bioassay-guided fractionation of the Okinawan marine cyanobacterium Okeania sp. led to the isolation of the novel cyclodepsipeptide odobromoamide (1). The gross structure of 1 was determined by spectroscopic analyses, and its absolute stereochemistry was determined using a variety of different methods, including chemical derivatization and degradation followed by HPLC analysis. In addition, odobromoamide (1) exhibited broad-spectrum cytotoxicity against a human cancer cell line panel.

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Isolation and Total Synthesis of Hoshinolactam, an Antitrypanosomal Lactam from a Marine Cyanobacterium

Ogawa Hidetoshi, Iwasaki Arihiro, Sumimoto Shimpei, Iwatsuki Masato, Ishiyama Aki, Hokari Rei, Otoguro Kazuhiko, Omura Satoshi, Suenaga Kiyotake

Organic Letters 19 ( 4 ) 890 - 893 2017.02

Accepted, ISSN 1523-7060

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Isolation and identification of two potential phytotoxic substances from the aquatic fern Marsilea crenata

Islam Md Shafiqul, Iwasaki Arihiro, Suenaga Kiyotake, Kato-Noguchi Hisashi

Journal of Plant Biology 60 ( 1 ) 75 - 81 2017.02

ISSN 1226-9239

Organic agriculture emphasized using of biologically originated herbicides and phytotoxic substances are being considered as a replacement to chemical herbicides. Marsilea crenata is an aquatic perennial fern distributed in the South-East Asian countries and is well known for various biological properties. However, to date, there has been no report that addresses the phytotoxicity of Marsilea crenata. Therefore, we explored phytotoxic properties and phytotoxic substances from Marsilea crenata. An aqueous methanol extracts of Marsilea crenata showed inhibition on the seedling growth of cress, lettuce, alfalfa, barnyard grass, Italian ryegrass, and foxtail fescue. Inhibition increased with increasing extract concentration. The extract was purified by several chromatographic steps and two phytotoxic substances were isolated and identified by spectroscopic analysis as loliolide and isololiolide. At the concentration of 30 μM, loliolide and isololiolide inhibited seedling growth of cress and barnyard grass by 41.3 to 51.1%, and 58.15 to 87.5% of control seedlings, respectively. The concentrations required for 50% inhibition of cress and barnyard grass seedlings ranged from 32.1 to 128.5 μM for loliolide, 37.0 to 176.2 μM for isololiolide. These results suggest these compounds may be responsible for phytotoxic effects of Marsilea crenata extract and could be an important part of organic agriculture.

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Total synthesis and stereochemical determination of yoshinone A

Shinomiya Seiichi, Iwasaki Arihiro, Ohno Osamu, Suenaga Kiyotake

Phytochemistry 132 109 - 114 2016.12

Accepted, ISSN 0031-9422

In 2014, the γ-pyrone-containing polyketide, yoshinone A, was isolated from the marine cyanobacterium Leptolyngbya sp. and its structure was determined. Yoshinone A inhibited differentiation of 3T3-L1 cells into adipocytes, with an EC₅₀ value of 420 nM without any cytotoxicity, and therefore is expected to be a lead compound for obesity drugs. To establish its absolute configuration, and to provide sufficient amounts for further research, the total synthesis of yoshinone A was achieved through synthesis of its two possible diastereomers.

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Total Synthesis of Miuraenamides A and D

Ojima Daisuke, Yasui Ayano, Tohyama Koh, Tokuzumi Keita, Toriihara Eisuke, Ito Kayoko, Iwasaki Arihiro, Tomura Tomohiko, Ojika Makoto, Suenaga Kiyotake

Journal of Organic Chemistry 81 ( 20 ) 9886 - 9894 2016.10

Accepted, ISSN 0022-3263

Miuraenamides A and D, cyclodepsipeptides with antimicrobial and antitumor activity, were synthesized. The synthesis of an unsaturated hydroxycarboxylic acid moiety, starting from a chiral epoxide, was achieved by Suzuki-Miyaura coupling as a key step. As a result, the overall yield for miuraenamide A over the longest linear sequence is 3.2%, while the yield of the previously reported procedure is 1.9%. In addition, the cell growth-inhibitory activity and anti-Phytophthora activity of the synthesized compounds were evaluated.

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Kanamienamide, an Enamide with an Enol Ether from the Marine Cyanobacterium Moorea bouillonii

Sumimoto Shimpei, Iwasaki Arihiro, Ohno Osamu, Sueyoshi Kosuke, Teruya Toshiaki, Suenaga Kiyotake

Organic Letters 18 ( 19 ) 4884 - 4887 2016.10

Accepted, ISSN 1523-7060

Kanamienamide, an enamide with an enol ether, was isolated from the marine cyanobacterium Moorea bouillonii. The gross structure was established by spectroscopic analyses, and the relative stereochemistry was elucidated on the basis of the analyses of NOESY correlations and ¹H-¹H coupling constants. The absolute configuration was determined on the basis of the chiral HPLC analysis of the N-Me-Leu derived from kanamienamide. This is the first report of a natural product that possesses an N-Me-enamide adjacent to an enol ether. Kanamienamide showed growth-inhibitory activity toward HeLa cells with an IC₅₀ value of 2.5 μM and induced apoptosis-like cell death.

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Urumamide, a novel chymotrypsin inhibitor with a β-amino acid from a marine cyanobacterium Okeania sp.

Kanamori Yuki, Iwasaki Arihiro, Sumimoto Shinpei, Suenaga Kiyotake

Tetrahedron Letters 57 ( 37 ) 4213 - 4216 2016.09

Accepted, ISSN 0040-4039

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Odoamide, a cytotoxic cyclodepsipeptide from the marine cyanobacterium Okeania sp.

Sueyoshi Kosuke, Kaneda Masato, Sumimoto Shinpei, Oishi Shinya, Fujii Nobutaka, Suenaga Kiyotake, Teruya Toshiaki

Tetrahedron 72 ( 35 ) 5472 - 5478 2016.09

Accepted, ISSN 0040-4020

The bioassay-guided fractionation of the Okinawan marine cyanobacterium Okeania sp. led to the isolation of the 26-membered cyclodepsipeptide odoamide (1). The gross structure of 1 was determined by 1D and 2D NMR analyses, whereas its absolute stereochemistry was determined using a variety of different methods, including synthesis and chemical degradation followed by chiral HPLC analysis. Notably, odoamide (1) showed potent cytotoxicity against HeLa S3 human cervical cancer cells with an IC₅₀ value of 26.3 nM.

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Allelopathic potential and an allelopathic substance in mango leaves

Suzuki Masahiko, Khan Md Sirajul Islam, Iwasaki Arihiro, Suenaga Kiyotake, Kato-Noguchi Hisashi

Acta Agriculturae Scandinavica - Section B Soil and Plant Science 67 ( 1 ) 37 - 42 2016.08

Accepted, ISSN 0906-4710

The present study was aimed to determine the allelopathic potential of mango (Mangifera indica L.) leaves and to identify allelopathic substances in the leaves. The aqueous methanol extracts of mango leaves inhibited seedling growth of garden cress, radish, rapeseed, foxtail fescue and crabgrass, and the inhibitory effects increased with the increasing extract concentration, suggesting that mango leaves may contain allelopathic substances. The extract was then purified by several chromatographic runs through a bioassay-directed fractionation, and an growth inhibitory substance was isolated and identified by spectral data as methyl-3,4,5-trihydroxybenzoate (methyl gallate). Methyl gallate at the concentration of 10 mM inhibited 98.6% and 99.8% of root and shoot growth of garden cress relative to the control, respectively, and 94.4% and 49.3% of those of foxtail fescue, respectively. The concentrations of methyl gallate required for 50% growth inhibition (I₅₀) on garden cress roots and shoots were 3.9 and 3.3 mM, and those on foxtail fescue roots and shoots were 1.5 and 9.5 mM, respectively. It is the first report of an allelopathic substance in mango leaves and allelopathic activity of methyl gallate. Therefore, the mango leaves may have potential as a soil additive material for the weed management options.

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Janadolide, a Cyclic Polyketide-Peptide Hybrid Possessing a tert-Butyl Group from an Okeania sp. Marine Cyanobacterium

Ogawa Hidetoshi, Iwasaki Arihiro, Sumimoto Shinpei, Kanamori Yuki, Ohno Osamu, Iwatsuki Masato, Ishiyama Aki, Hokari Rei, Otoguro Kazuhiko, Omura Satoshi, Suenaga Kiyotake

Journal of Natural Products 79 ( 7 ) 1862 - 1866 2016.07

Accepted, ISSN 0163-3864

Janadolide, a new cyclic polyketide-peptide hybrid possessing a tert-butyl group, was isolated from an Okeania sp. marine cyanobacterium. The gross structure was elucidated by spectroscopic analyses, and the absolute configurations of the amino acid moieties were determined by acid hydrolysis and chiral-phase HPLC analyses. The absolute configuration of the two stereogenic centers in the polyketide moiety was elucidated based on a combination of degradation reactions and spectroscopic analyses including the phenyl-glycine methyl ester method. Janadolide showed potent antitrypanosomal activity with an IC₅₀ value of 47 nM without cytotoxicity against human cells at 10 μM.

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Total synthesis and absolute configuration of koshikalide

Kunifuda Kazuki, Iwasaki Arihiro, Nagamoto Masashi, Suenaga Kiyotake

Tetrahedron Letters 57 ( 29 ) 3121 - 3123 2016.07

Accepted, ISSN 0040-4039

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Total Synthesis of Biselyngbyolide B

Sato Eisuke, Tanabe Yurika, Nakajima Naoya, Ohkubo Akifumi, Suenaga Kiyotake

Organic Letters 18 ( 9 ) 2047 - 2049 2016.05

Accepted, ISSN 1523-7060

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Immunological Adjuvant Activity of Pectinioside A, the Steroidal Saponin from the Starfish Patiria pectinifera

Kawase Osamu, Ohno Osamu, Suenaga Kiyotake, Xuan Xuenan

Natural Product Communications 11 ( 5 ) 605 - 606 2016.05

Accepted, ISSN 1934-578X

A Potent Phytotoxic Substance in Aglaia odorata Lour.

Kato-Noguchi Hisashi, Suzuki Masahiko, Noguchi Kazutaka, Ohno Osamu, Suenaga Kiyotake, Laosinwattana Chamroon

Chemistry and Biodiversity 13 ( 5 ) 549 - 554 2016.05

Accepted, ISSN 1612-1872

Aglaia odorata Lour. (Meliaceae) was found to have very strong allelopathic activity and a bioherbicide PORGANIC^™ was developed from its leaf extracts. However, the phytotoxic substances causing the strong allelopathic activity of the plants have not yet been determined. Therefore, we investigated allelopathic properties and phytotoxic substances in A. odorata. Aqueous EtOH extracts of A. odorata leaves inhibited root and shoot growth of garden cress (Lepidum sativum), lettuce (Lactuca sativa), alfalfa (Medicago sativa), timothy (Phleum pratense), ryegrass (Lolium multiflorum), and Echinochloa crus-galli with the extract concentration-dependent manner. The extracts were then purified and a major phytotoxic substance with allelopathic activity was isolated and identified by spectral data as rocaglaol. Rocaglaol inhibited the growth of garden cress and E. crus-galli at concentrations > 0.3 and 0.03 μm, respectively. The concentrations required for 50% inhibition ranged from 0.09 to 2.5 μm. The inhibitory activity of rocaglaol on the weed species, E. crus-galli, was much greater than that of abscisic acid. These results suggest that rocaglaol may be a major contributor to the allelopathic effect of A. odorata and bioherbicide PORGANIC^™.

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Anti-obesity activities of the yoshinone A and the related marine γ-pyrone compounds

Koyama Tomoyuki, Kawazoe Yoshinori, Iwasaki Arihiro, Ohno Osamu, Suenaga Kiyotake, Uemura Daisuke

Journal of Antibiotics 69 ( 4 ) 348 - 351 2016.04

Accepted, ISSN 0021-8820

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Structural optimization of 10-methyl-aplog-1, a simplified analog of debromoaplysiatoxin, as an anticancer lead

Kikumori Masayuki, Yanagita Ryo C., Tokuda Harukuni, Suenaga Kiyotake, Nagai Hiroshi, Irie Kazuhiro

Bioscience, Biotechnology and Biochemistry 80 ( 2 ) 221 - 231 2016.02

Accepted, ISSN 0916-8451

Aplog-1 is a simplified analog of debromoaplysiatoxin (DAT) with potent tumor-promoting and proinflammatory activities. Aplog-1 and DAT exhibited anti-proliferative activities against several human cancer cell lines, whereas aplog-1 did not have tumor-promoting nor proinflammatory activities. We have recently found 10-methyl-aplog-1 (1) to have strong anti-proliferative activity compared with aplog-1. To further investigate the structural factors involved in the tumor-promoting, proinflammatory, and anti-proliferative activities, two dimethyl derivatives of aplog-1 (2, 3) were synthesized, where two methyl groups were installed at positions 4 and 10 or 10 and 12. 10,12-Dimethyl-aplog-1 (2) had stronger inhibitory effects on the growth of several human cancer cell lines than 1 and DAT, but exhibited no tumor-promoting and proinflammatory activities. In contrast, 4,10-dimethyl-aplog-1 (3) displayed weak tumor-promoting and proinflammatory activities along with anti-proliferative activity similar to that of 1 and DAT. Compound 2 would be the optimized seed for anticancer drugs among the simplified analogs of DAT.

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Isolation and Structure of Kurahyne B and Total Synthesis of the Kurahynes

Okamoto Shinichiro, Iwasaki Arihiro, Ohno Osamu, Suenaga Kiyotake

Journal of Natural Products 78 ( 11 ) 2719 - 2725 2015.11

Accepted, ISSN 0163-3864

Kurahyne B (2), a new analogue of kurahyne (1), was isolated from the marine cyanobacterium Okeania sp. Its gross structure was elucidated based on spectroscopic analyses, and the absolute configuration was established by total synthesis. Kurahyne B (2) inhibited the growth of both HeLa and HL60 cells, with IC₅₀ values of 8.1 and 9.0 μM, respectively. The growth-inhibitory activity of kurahyne B was the same as kurahyne (1). In parallel, the first total synthesis of kurahyne (1) was also achieved.

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Identification of a molecular target of kurahyne, an apoptosis-inducing lipopeptide from marine cyanobacterial assemblages

Iwasaki Arihiro, Ohno Osamu, Katsuyama Shun, Morita Maho, Sasazawa Yukiko, Dan Shingo, Simizu Siro, Yamori Takao, Suenaga Kiyotake

Bioorganic and Medicinal Chemistry Letters 25 ( 22 ) 5295 - 5298 2015.11

Accepted, ISSN 0960-894X

In 2014, we isolated kurahyne, an acetylene-containing lipopeptide, from a marine cyanobacterial assemblage of Lyngbya sp. Kurahyne exhibited growth-inhibitory activity against human cancer cells, and induced apoptosis in HeLa cells. However, its mode of action is not yet clear. To elucidate its mode of action, we carried out several cell-based assays, and identified the intracellular target molecule of kurahyne as sarco/endoplasmic reticulum Ca²⁺ ATPase (SERCA). In addition, we found that kurahyne inhibited the differentiation of macrophages into osteoclasts.

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Structures and Biological Activities of Novel Biselyngbyaside Analogs Isolated from the Marine Cyanobacterium Lyngbya sp.

Watanabe, Ayane, Ohno, Osamu, Morita, Maho, Inuzuka, Toshiyasu, Suenaga, Kiyotake

BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN 88 ( 9 ) 1256 - 1264 2015.09

Research paper (scientific journal), ISSN 0009-2673

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Synthesis and structure-activity relationships for cytotoxicity and apoptosis-inducing activity of (+)-halichonine B

Hayakawa Ichiro, Nakamura Tomomi, Ohno Osamu, Suenaga Kiyotake, Kigoshi Hideo

Organic and Biomolecular Chemistry 13 ( 39 ) 9969 - 9976 2015.08

Accepted, ISSN 1477-0520

Halichonine B is a sesquiterpene alkaloid isolated from the marine sponge Halichondria okadai Kadota. Halichonine B has exhibited cytotoxicity against mammalian cancer cells and induced apoptosis in the human leukemia cell line HL60. Here we established a practical route for the synthesis of halichonine B and its analogues, and we evaluated their biological activities. It was revealed that the secondary amino groups in the side chain portion are important for the strong cytotoxicity of halichonine B and that the N11-prenyl group is unimportant. Halichonine B and its analogues were also observed to induce apoptosis in HL60 cells.

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Isolation of Monovalerianester A, an Inhibitor of Fat Accumulation, from Valeriana fauriei

Yuki Keiji, Ikeda Mariko, Yoshida Shosuke, Ohno Osamu, Suenaga Kiyotake, Yamada Kaoru, Uemura Daisuke, Miyamoto Kenji

Natural Product Communications 10 ( 8 ) 1333 - 1334 2015.08

Accepted, ISSN 1934-578X

The rhizomes and roots of Valeriana fauriei were extracted with 80% aqueous ethanol. This extract was found to exhibit potent inhibitory effects on fat accumulation in 3T3-LI murine adipocytes. After several steps of chromatographic purification, we succeeded in identifying monovalerianester A as an inhibitor of fat accumulation. Thus, monovalerianester A and the crude extract of the rhizomes and roots of V. fauriei may have therapeutic potential for the treatment of obesity.

Total synthesis and stereochemical reassignment of maedamide

Takayanagi Ayano, Iwasaki Arihiro, Suenaga Kiyotake

Tetrahedron Letters 56 ( 34 ) 4947 - 4949 2015.05

Accepted, ISSN 0040-4039

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Biselyngbyasides, cytotoxic marine macrolides, are novel and potent inhibitors of the Ca²⁺ pumps with a unique mode of binding

Morita Maho, Ogawa Haruo, Ohno Osamu, Yamori Takao, Suenaga Kiyotake, Toyoshima Chikashi

FEBS Letters 589 ( 13 ) 1406 - 1411 2015.05

Accepted, ISSN 0014-5793

Biselyngbyasides (BLSs), macrolides from a marine cyanobacterium, are cytotoxic natural products whose target molecule is unknown. Here we report that BLSs are high affinity (K<inf>i</inf> ∼ 10 nM) inhibitors of Ca2+-pumps with a unique binding mode. The crystal structures of the Ca2+-pump in complex with BLSs at 3.2-3.5 Å-resolution show that BLSs bind to the pump near the cytoplasmic surface of the transmembrane region. The crystal structures and activity measurement of BLS analogs allow us to identify the structural features that confer high potency to BLSs as inhibitors of the pump.

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Isolation and Identification of an Allelopathic Substance from Hibiscus sabdariffa

Suwitchayanon, Prapaipit, Pukclai, Piyatida, Ohno, Osamu, Suenaga, Kiyotake, Kato-Noguchi, Hisashi

Natural Product Communications 10 ( 5 ) 765 - 770 2015.05

Research paper (scientific journal), ISSN 1934-578X

Mebamamides A and B, Cyclic Lipopeptides Isolated from the Green Alga Derbesia marina

Iwasaki Arihiro, Ohno Osamu, Sumimoto Shinpei, Matsubara Teruhiko, Shimada Satoshi, Sato Toshinori, Suenaga Kiyotake

Journal of Natural Products 78 ( 4 ) 901 - 908 2015.04

Accepted, ISSN 0163-3864

Mebamamides A and B, new lipopeptides with four d-amino acid residues and a 3,8-dihydroxy-9-methyldecanoic acid residue, were isolated from the green alga Derbesia marina. Their gross structures were elucidated by spectroscopic and ESI-ITMS analyses. The absolute configurations except for the two leucines were revealed based on chiral-phase HPLC analyses of the acid hydrolysate and a modified Mosher's method. A distinction between d-Leu and l-Leu in the sequence was established by the application of a dansyl-Edman method to the partial acid hydrolysate. Mebamamide A did not exhibit any growth inhibitory activity against HeLa and HL60 cells at 10 μM, and mebamamide B did not exhibit any growth inhibitory activity against those cells at 100 μM. Additionally, it was suggested that mebamamide B induced the differentiation of HL60 cells into macrophage-like cells at 100 μM. (Chemical Equation).

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A phytotoxic active substance in the decomposing litter of the fern Gleichenia japonica

Kato-Noguchi Hisashi, Saito Yoshihumi, Ohno Osamu, Suenaga Kiyotake

Journal of Plant Physiology 176 55 - 60 2015.03

Accepted, ISSN 0176-1617

The fern Gleichenia japonica often dominates plant communities by forming large monospecific stands throughout the temperate to tropical Asia. The objective of this study was the investigation of allelopathic property and substances of the decomposing litter of the fern to evaluate the possible involvement of its allelopathy in the domination. An aqueous methanol extract of G. japonica litter inhibited the growth of garden cress (Lepidium sativum), lettuce (Lactuca sativa), barnyard grass (Echinochloa crus-galli), and ryegrass (Lolium multiflorum). This result suggests that G. japonica litter contains growth inhibitory substances. The extract was purified by chromatography while monitoring the inhibitory activity, and a growth inhibitory substance was isolated. The chemical structure of the substance was determined by spectral data to be a novel compound, 13-. O-β-fucopyranosyl-3β-hydroxymanool. This compound inhibited root and shoot growth of garden cress and barnyard grass at concentrations ranging from 89.7 to 271. μM for 50% inhibition. In addition, the compound had potent growth inhibitory activity with the soil taken from near the colony. The concentration of the compound in soil under a pure colony of G. japonica was 790. μM, suggesting that the compound may contribute to the establishment of monocultural stands by this fern.

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Jahanyne, an apoptosis-inducing lipopeptide from the marine cyanobacterium lyngbya sp.

Iwasaki Arihiro, Ohno Osamu, Sumimoto Shinpei, Ogawa Hidetoshi, Nguyen Kim Anh, Suenaga Kiyotake

Organic Letters 17 ( 3 ) 652 - 655 2015.02

Accepted, ISSN 1523-7060

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An inhibitor of the adipogenic differentiation of 3T3-L1 cells, yoshinone A, and its analogs, isolated from the marine cyanobacterium Leptolyngbya sp.

Inuzuka Toshiyasu, Yamamoto Keita, Iwasaki Arihiro, Ohno Osamu, Suenaga Kiyotake, Kawazoe Yoshinori, Uemura Daisuke

Tetrahedron Letters 55 ( 49 ) 6711 - 6714 2014.12

Accepted, ISSN 0040-4039

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Suaveolic Acid: A Potent Phytotoxic Substance of Hyptis suaveolens.

Islam A. K M Mominul, Ohno Osamu, Suenaga Kiyotake, Kato-Noguchi Hisashi

Scientific World Journal 2014 Article ID 425942 (6 pages) 2014.10

Accepted, ISSN 2356-6140

Hyptis suaveolens (Lamiaceae) is an exotic invasive plant in many countries. Earlier studies reported that the aqueous, methanol, and aqueous methanol extract of H. suaveolens and its residues have phytotoxic properties. However, to date, the phytotoxic substances of this plant have not been reported. Therefore, the objectives of this study were isolation and identification of phytotoxic substances of H. suaveolens. Aqueous methanol extract of this plant was purified by several chromatographic runs through bioassay guided fractionation using garden cress (Lepidium sativum) as a test plant. Final purification of a phytotoxic substance was achieved by reverse phase HPLC and characterized as 14α-hydroxy-13β-abiet-8-en-18-oic acid (suaveolic acid) by high-resolution ESI-MS, ¹H-,¹³C-NMR, CD, and specific rotation. Suaveolic acid inhibited the shoot growth of garden cress, lettuce (Lactuca sativa), Italian ryegrass (Lolium multiflorum), and barnyard grass (Echinochloa crus-galli) at concentrations greater than 30 μM. Root growth of all but lettuce was also inhibited at concentrations greater than 30 μM. The inhibitory activities were concentration dependent. Concentrations required for 50% growth inhibition of suaveolic acid for those test plant species were ranged from 76 to 1155 μM. Therefore, suaveolic acid is phytotoxic and may be responsible for the phytotoxicity of H. suaveolens plant extracts.

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Maedamide, a novel chymotrypsin inhibitor from a marine cyanobacterial assemblage of Lyngbya sp.

Iwasaki Arihiro, Ohno Osamu, Sumimoto Shinpei, Suda Shoichiro, Suenaga Kiyotake

Tetrahedron Letters 55 ( 30 ) 4126 - 4128 2014.07

Accepted, ISSN 0040-4039

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Two novel phytotoxic substances from Leucas aspera

Islam A. K M Mominul, Ohno Osamu, Suenaga Kiyotake, Kato-Noguchi Hisashi

Journal of Plant Physiology 171 ( 11 ) 877 - 883 2014.07

Accepted, ISSN 0176-1617

Leucas aspera (Lamiaceae), an aromatic herbaceous plant, is well known for many medicinal properties and a number of bioactive compounds against animal cells have been isolated. However, phytotoxic substances from L. aspera have not yet been documented in the literature. Therefore, current research was conducted to explore the phytotoxic properties and substances in L. aspera. Aqueous methanol extracts of L. aspera inhibited the germination and growth of garden cress (Lepidum sativum) and barnyard grass (Echinochloa crus-galli), and the inhibitory activities were concentration dependent. These results suggest that the plant may have phytotoxic substances. The extracts were then purified by several chromatographic runs. The final purification was achieved by reversed-phase HPLC to give an equilibrium (or inseparable) 3:2 mixture of two labdane type diterpenes (compounds 1 and 2). These compounds were characterized as (rel 5S,6R,8R,9R,10S,13S,15S,16R)-6-acetoxy-9,13;15,16-diepoxy-15-hydroxy-16-methoxylabdane (1) and (rel 5S,6R,8R,9R,10S,13S,15R,16R)-6-acetoxy-9,13;15,16-diepoxy-15-hydroxy-16-methoxylabdane (2) by spectroscopic analyses. A mixture of the two compounds inhibits the germination and seedling growth of garden cress and barnyard grass at concentrations greater than 30 and 3μM, respectively. The concentration required for 50% growth inhibition (I₅₀) of the test species ranges from 31 to 80μM, which suggests that the mixture of these compounds, are responsible for the phytotoxic activity of L. aspera plant extract.

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Growth limiting effects on various terrestrial plant species by an allelopathic substance, loliolide, from water hyacinth

Kato-Noguchi, Hisashi, Moriyasu, Mayumi, Ohno, Osamu, Suenaga, Kiyotake

AQUATIC BOTANY 117 56 - 61 2014.07

Research paper (scientific journal), Accepted, ISSN 0304-3770

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Isolation and identification of a plant growth inhibitor from Tinospora tuberculata Beumee

Kato-Noguchi Hisashi, Pukclai Piyatida, Ohno Osamu, Suenaga Kiyotake

Acta Physiologiae Plantarum 36 ( 7 ) 1621 - 1626 2014.07

Accepted, ISSN 0137-5881

Tinospora tuberculata Beumee has been used widely as a folk medicine and several bioactive compounds have been isolated. However, no herbicidal compound has been reported in this species. Therefore, we investigated the presence of phytotoxins in T. tuberculata. The aqueous methanol extracts of T. tuberculata inhibited the growth of roots and shoots of cress (Lepidum sativum L.), lettuce (Lactuca sativa L.), timothy (Phleum pratense L.) and barnyard grass (Echinochloa crus-galli (L.) Beauv.). The extract was then purified by several chromatographic runs with monitoring the inhibitory activity and the main phytotoxic substance was isolated. The chemical structure of the compound was determined by spectral data as syringin (4-[(1E)-3-Hydroxyprop-1-en-1-yl]-2,6-dimethoxyphenyl β-d-glucopyranoside). It inhibited the root and shoot growth of all test plant species at concentrations >10 μM. The concentrations required for 50 % inhibition of root and shoot growth of cress and lettuce ranged from 78.2 to 412 μM, and that of timothy and barnyard grass renged from 9.8 to 73.2 μM. Effectiveness of syringin on monocotyledonous (timothy and barnyard grass) plants was greater than that on dicotyledonous (cress and lettuce) plants. These results suggest that syringin may contribute to the allelopathic effect caused by the T. tuberculata extract.

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Total synthesis of biselyngbyolide A

Tanabe Yurika, Sato Eisuke, Nakajima Naoya, Ohkubo Akifumi, Ohno Osamu, Suenaga Kiyotake

Organic Letters 16 ( 11 ) 2858 - 2861 2014.06

Accepted, ISSN 1523-7060

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Nimbolide B and Nimbic Acid B, Phytotoxic Substances in Neem Leaves with Allelopathic Activity

Kato-Noguchi, Hisashi, Salam, Md Abdus, Ohno, Osamu, Suenaga, Kiyotake

MOLECULES 19 ( 6 ) 6929 - 6940 2014.06

Research paper (scientific journal), Accepted, ISSN 1420-3049

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Kurahamide, a cyclic depsipeptide analog of dolastatin 13 from a marine cyanobacterial assemblage of Lyngbya sp.

Iwasaki Arihiro, Sumimoto Shinpei, Ohno Osamu, Suda Shoichiro, Suenaga Kiyotake

Bulletin of the Chemical Society of Japan 87 ( 5 ) 609 - 613 2014.05

Accepted, ISSN 0009-2673

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Phytotoxic substances with allelopathic activity may be central to the strong invasive potential of Brachiaria brizantha

Kato-Noguchi Hisashi, Kobayashi Ai, Ohno Osamu, Kimura Fukiko, Fujii Yoshiharu, Suenaga Kiyotake

Journal of Plant Physiology 171 ( 7 ) 525 - 530 2014.04

Accepted, ISSN 0176-1617

The grass Brachiaria brizantha, native to eastern Africa, becomes naturalized and dominant quickly in the non-native areas. It was hypothesized that phytotoxic chemical interaction between this plant and native plants may play an important role in the invasion of B. brizantha. However, no potent phytotoxic substance has been reported in this species. Therefore, we investigated possible allelopathic activity and searched for phytotoxic substances with allelopathic activity in B. brizantha. An aqueous methanol extract of B. brizantha inhibited the growth of roots and shoots of garden cress (Lepidium sativum), lettuce (Lactuca sativa), timothy (Phleum pratense) and ryegrass (Lolium multiflorum) seedlings. The extract was purified by several chromatographic runs and three allelopathically active substances were isolated and identified by spectral analysis as (6R,. 9R)-3-oxo-α-ionol, (6R,. 9S)-3-oxo-α-ionol and 4-ketopinoresinol. (6R,. 9R)-3-Oxo-α-ionol and (6R,. 9S)-3-oxo-α-ionol inhibited root and shoot growth of garden cress at concentrations greater than 30 and 10. μM, respectively. The activity of (6R,. 9S)-3-oxo-α-ionol was 5.3- to 6.2-fold that of (6R,. 9R)-3-oxo-α-ionol. The stereochemistry of the hydroxyl group at position C-9 may be important for the inhibitory activities of those compounds. 4-Ketopinoresinol inhibited root and shoot growth of garden cress at concentrations greater than 30. μM. The growth inhibitory activity of (6R,. 9S)-3-oxo-α-ionol was the greatest and followed by 4-ketopinoresinol and (6R,. 9R)-3-oxo-α-ionol. These results suggest that those phytotoxic substances may contribute to the allelopathic effect caused by B. brizantha and may be involved in the invasion of B. brizantha.

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Biselyngbyolide B, a Novel ER Stress-inducer Isolated from the Marine Cyanobacterium Lyngbya sp.

Osamu Ohno, Ayane Watanabe, Maho Morita, and Kiyotake Suenaga

Chemistry Letters 43 ( 3 ) 287-289 2014.03

Research paper (scientific journal), Accepted

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Kurahyne, an acetylene-containing lipopeptide from a marine cyanobacterial assemblage of Lyngbya sp.

Arihiro Iwasaki, Osamu Ohno, Shinpei Sumimoto, Shoichiro Suda, and Kiyotake Suenaga

RSC Advances 4 12840-12843 2014.02

Research paper (scientific journal), Joint Work, Accepted

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A novel substance with allelopathic activity in Ginkgo biloba

Kato-Noguchi Hisashi, Takeshita Sayaka, Kimura Fukiko, Ohno Osamu, Suenaga Kiyotake

Journal of Plant Physiology 170 ( 18 ) 1595 - 1599 2013.12

Accepted, ISSN 0176-1617

Ginkgo (Ginkgo biloba) is one of the oldest living tree species and has been widely used in traditional medicine. Leaf extracts of ginkgo, such as the standardized extract EGb761, have become one of the best-selling herbal products. However, no bioactive compound directed at plants has been reported in this species. Therefore, we investigated possible allelopathic activity and searched for allelopathically active substances in ginkgo leaves. An aqueous methanol leaf extract inhibited the growth of roots and shoots of garden cress (Lepidium sativum), lettuce (Lactuca sativa), timothy (Phleum pratense) and ryegrass (Lolium multiflorum) seedlings. The extract was purified by several chromatographic runs and an allelopathically active substance was isolated and identified by spectral analysis to be the novel compound 2-hydroxy-6-(10-hydroxypentadec-11-enyl)benzoic acid. The compound inhibited root and shoot growth of garden cress and timothy at concentrations greater than 3. μM. The activity of the compound was 10- to 52-fold that of nonanoic acid. These results suggest that 2-hydroxy-6-(10-hydroxypentadec-11-enyl)benzoic acid may contribute to the allelopathic effect caused by ginkgo leaf extract. The compound may also have potential as a template for the development of new plant control substances.

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Isolation and identification of an allelopathic substance from duckweed (Lemna minor L.)

Tran Thi Ngoc Bich, Osamu Ohno, Kiyotake Suenaga, and Hisashi Kato-Noguchi

Allelopathy Journal 32 ( 2 ) 213 - 222 2013.10

Research paper (scientific journal), Joint Work, Accepted

Effects of the methoxy group in the side chain of debromoaplysiatoxin on its tumor-promoting and anti-proliferative activities

Yanagita Ryo C., Kamachi Hiroaki, Kikumori Masayuki, Tokuda Harukuni, Suzuki Nobutaka, Suenaga Kiyotake, Nagai Hiroshi, Irie Kazuhiro

Bioorganic and Medicinal Chemistry Letters 23 ( 15 ) 4319 - 4323 2013.08

Accepted, ISSN 0960-894X

Debromoaplysiatoxin (DAT) is a tumor promoter isolated from sea hare and exhibits anti-proliferative activity against several cancer cell lines. To clarify key residues that are responsible for its tumor-promoting activity, we focused on the chiral methoxy group in the side chain, whose role had not yet been discussed or examined before. Demethoxy-DAT (8) was derived from DAT and we evaluated its tumor-promoting activity, anti-proliferative activity, and ability to bind to protein kinase C (PKC) isozymes. Compound 8 showed somewhat weaker tumor-promoting activity than that of DAT both in vitro and in vivo, but showed higher anti-proliferative activity against several cancer cell lines. Although the affinity to novel PKC isozymes of 8 was comparable to that of DAT, the affinity to conventional PKC isozymes decreased slightly. These results suggest that the methoxy group of DAT is one of the key residues critical for tumor-promoting activity but not for anti-proliferative activity. Since the methoxy group has little influence on the molecular hydrophobicity, this is the first report showing that structural factors other than hydrophobicity in the side chain of DAT affected its biological activities.

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Allelopathy is involved in the formation of pure colonies of the fern Gleichenia japonica

Kato-Noguchi Hisashi, Saito Yoshihumi, Ohno Osamu, Suenaga Kiyotake

Journal of Plant Physiology 170 ( 6 ) 577 - 582 2013.04

Accepted, ISSN 0176-1617

The fern Gleichenia japonica is one of the most widely distributed fern and occurs throughout East to South Asia. The species often dominates plant communities by forming large monospecific colonies. However, the potential mechanism for this domination has not yet been described. The objective of this study was to test the hypothesis that allelochemicals are involved in the formation of G. japonica colonies. An aqueous methanol extract of G. japonica inhibited the growth of seedlings of garden cress (Lepidium sativum), lettuce (Lactuca sativa), ryegrass (Lolium multiflorum) and timothy (Phleum pratense). Increasing extract concentration increased the inhibition. These results suggest that G. japonica contain allelopathic substances. The extract was then purified by several chromatographies with monitoring the inhibitory activity and two growth inhibitory substances causing the allelopathic effect were isolated. The chemical structures of the two substances were determined by spectral data to be a novel compound 3- O-β-allopyranosyl-13- O-β-fucopyranosyl-3β-hydroxymanool (1) and 18- O-α- l-rhamnopyranosyl-(1→2)-β- d-glucopyranosyl-13-epitorreferol (2). These compounds inhibited the shoot and root growth of garden cress, lettuce, alfalfa (Medicago sativa), timothy, ryegrass and barnyardgrass (Echinochloa crus-galli) at concentrations greater than 0.1-1.0 mM. The concentrations required for 50% growth inhibition of root and shoot growth of these test plants ranged from 0.72 to 3.49 mM and 0.79 to 3.51 mM for compounds 1 and 2, respectively. Concentration of compounds 1 and 2 in soil under the pure colony of G. japonica was 4.9 and 5.7 mM, respectively, indicating concentrations over those required for 50% growth inhibition are potentially available under monocultural stands of these ferns. Therefore, these compounds may contribute to the allelopathic effects caused by presence of G. japonica and may thus contribute to the establishment of monocultural stands by this fern.

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Total synthesis, structural elucidation, and structure-cytotoxic activity relationship of (-)-gummiferol

Takamura Hiroyoshi, Wada Hiroko, Lu Nan, Ohno Osamu, Suenaga Kiyotake, Kadota Isao

Journal of Organic Chemistry 78 ( 6 ) 2443 - 2454 2013.03

Accepted, ISSN 0022-3263

A highly stereoselective and stereodivergent synthesis of two possible diastereomers of (-)-gummiferol was achieved, wherein the stepwise epoxidation and Cadiot-Chodkiewicz reaction were utilized for the construction of the diepoxide moiety and triacetylene part, respectively. Detailed comparison of their ¹H and ¹³C NMR data and specific rotation with those of the natural product unambiguously elucidated the absolute stereostructure of gummiferol. In addition, the cytotoxic activity of the synthesized gummiferol, its stereoisomers, and its truncated analogues was evaluated, which clearly indicates that (1) the absolute configuration of the diepoxide moiety has little influence on the cytotoxic activity against human cancer cells and (2) the triacetylene unit is the crucial structural element required for exerting the cytotoxic activity.

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Apoptosis-inducing activity of the actin-depolymerizing agent aplyronine A and its side-chain derivatives

Ohno Osamu, Morita Maho, Kitamura Kazuhiro, Teruya Toshiaki, Yoneda Kozo, Kita Masaki, Kigoshi Hideo, Suenaga Kiyotake

Bioorganic and Medicinal Chemistry Letters 23 ( 5 ) 1467 - 1471 2013.03

Accepted, ISSN 0960-894X

Aplyronine A (1) and mycalolide B (2), which are cytotoxic actin-depolymerizing marine macrolides, were revealed to induce apoptosis in human leukemia HL60 cells and human epithelial carcinoma HeLa S₃ cells. Based on these results, actin-depolymerizing compounds were expected to exhibit apoptosis-inducing activity in cancer cells. Compounds 3-6, which were synthesized based on the side-chain structure of aplyronine A, were evaluated for their actin-depolymerizing activities in vitro and cytotoxicities against HL60 cells. The growth-inhibitory activities of 3-6 were well correlated with their actin-depolymerizing activities, and derivative 6 was shown to induce the disruption of actin filaments and apoptosis in HL60 cells. These results suggested that actin-depolymerizing agents 1, 2, and 6-induced apoptosis in HL60 cells may have been due to their actin-depolymerizing activity.

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A novel allelopathic substance, 13-epi-orthosiphol N, in Orthosiphon stamineus

Kato-Noguchi Hisashi, Hamada Naoko, Morita Maho, Suenaga Kiyotake

Journal of Plant Physiology 170 ( 1 ) 1 - 5 2013.01

Accepted, ISSN 0176-1617

Orthosiphon stamineus (Java tea) has been widely used as traditional herb and several bioactive compounds against animal cells have been isolated. However, no bioactive compound against plants has been reported. Therefore, we investigated possible allelopathic properties and substances in O. stamineus. Aqueous methanol extracts of O. stamineus inhibited root and hypocotyl growth of cress (Lepidium sativum) and lettuce (Lactuca sativa) seedlings. Increasing the extract concentration increased the inhibition, which suggests that O. stamineus may have allelopathic properties. When the extract was divided into an ethyl acetate and an aqueous fraction, the ethyl acetate fraction showed the stronger inhibitory effect. Thus, the ethyl acetate phase was further purified, and the main allelopathic substance was isolated and identified as 13- epi-orthosiphol N, a novel compound, by spectral data. 13- epi-Orthosiphol N inhibited root and hypocotyl growth of cress and lettuce at concentrations greater than 10 μmol/L. The concentrations required for 50% inhibition ranged from 41 to 102 μmol/L. These results suggest that 13- epi-orthosiphol N may be an allelochemical and main contributor to the growth inhibitory effect of O. stamineus and may have potential as a template for the development of new plant control substances.

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Bisebromoamide, an extract from Lyngbya species, induces apoptosis through ERK and mTOR inhibitions in renal cancer cells.

Kenjiro Suzuki, Ryuichi Mizuno, Kiyotake Suenaga, Toshiaki Teruya, Nobuyuki Tanaka, Takeo Kosaka, Mototsugu Oya:

Cancer Medicine 2 ( 1 ) 32-39 2013

Research paper (scientific journal), Joint Work, Accepted

Apoptosis as a practical target for identifying anticancer agents of marine origin

Ohno Osamu, Teruya Toshiaki, Suenaga Kiyotake, Uemura Daisuke

Forum on Immunopathological Diseases and Therapeutics 4 ( 1 ) 33 - 41 2013

Accepted, ISSN 2151-8017

Natural products and their synthetic analogs are widely used as anticancer drugs. Many anticancer drugs originated from cytotoxic compounds, and most have been shown to induce apoptosis in cancer cells. Based on the variety of their modes of action, the identification of new cytotoxic compounds may lead to the discovery of new types of drugs. Recently, much attention has been given to the metabolites of marine organisms due to their strong cytotoxicity. For example, eribulin mesylate, a synthetic analog of halichondrin B isolated from H. okadai Kadota, has been developed as an anticancer drug. Novel cytotoxic substances, such as halichonines, bisebromoamides, and biselyngbyasides, have been isolated from marine organisms as apoptosis-inducing agents. All of these compounds may possess therapeutic potential, and thus, efforts to identify new apoptosis-inducing agents of marine origin may contribute to the discovery of new pharmaceuticals.

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Genetic diversity of filamentous cyanobacteria from shore regions of Okinawa

Suda Shoichiro, Moriya Rui, Sumimoto Shinpei, Ohno Osamu, Suenaga Kiyotake

Journal of Marine Science and Technology (Taiwan) 21 ( SUPPL ) 175 - 180 2013

Accepted, ISSN 1023-2796

Benthic marine cyanobacteria are ubiquitous oxygenic photosynthetic bacteria and they form major components of various communities, including epiphytic, epilithic and microbial mats, in coral reef environments. Filamentous groups may form almost monospecific macroscopic colonies, and sometimes make potentially harmful algal blooms (HABs). HABs bring serious problems for marine tourism but marine filamentous cyanobacteria are good resource for drug discovery. However, cultivation and identification of such filamentous cyanobacteria are difficult and there are taxonomic confusions. In this study, we investigate 17 samples from coral reef area of 10 localities in Okinawa. Macroscopic mats or cushions of filamentous cyanobacteria were collected. The samples were divided into three parts: (1) for morphological observation, (2) for molecular work, and (3) cultivation for further study. Dominant cyanobacteira of each sample identified morphologically as Anabaena, Hydrocoleum, Lyngbya, Oscillatoria, Phormidium, Schizothrix and Symploca. Molecular results of partial 16S rDNA sequences revealed six groups that composed of heterocystous group, Leptolyngbya group, Symploca group, Moorea group, Oscillatoria group and unknown group, respectively. Some samples corroborated between morphology and molecular results but some were not. In addition, four out of six groups closely related with natural product producers. These results suggest that there are high biodiversity of marine benthic filamentous cyanobacteria in Okinawa that may become seeds of HABs as well as providing promising resources for drug discovery.

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Involvement of allelopathy in the establishment of pure colony of Dicranopteris linearis

Kato-Noguchi Hisashi, Saito Yoshihumi, Suenaga Kiyotake

Plant Ecology 213 ( 12 ) 1937 - 1944 2012.12

Accepted, ISSN 1385-0237

The fern Dicranopteris linearis Underw. (Old world forkedfern, Gleicheniaceae), the most widely distributed fern throughout tropical to temperature regions, dominates and often forms large pure colonies. Allelopathic chemical interaction of the fern was speculated to play an important role in the dominance. However, potential mechanisms, in particular, the allelopathic substance have not been reported. The objective of this study was the identification of its potential allelopathic substance and the evaluation of the ecological role of the substance. Extracts of D. linearis had an inhibitory effect on Echinochloa colonum and Avena fatua which are found near colonies of D. linearis in natural ecosystems. The extract was purified and a main inhibitory substance was isolated. The chemical structure of the substance was determined by high-resolution MS, and ¹H- and ¹³C-NMR spectral data and optical rotation as epicatechin-(2β → O → 7,4β → 8)-epicatechin-(4β → 8)-epicatechin (cinnamtannin B-1). Cinnamtannin B-1 inhibited the shoot and root growth of A. fatua and E. colonum at concentrations greater than 0. 2-0. 5 mM, and the concentrations required for 50 % growth inhibition on shoot and root growth of these plants were 0. 34-1. 31 mM. Cinnamtannin B-1 was found in soil under the colony, at concentrations of 4. 3 and 14. 5 mM in soil at the edge of and under the colony, respectively. These concentrations were over the concentration required for 50 % growth inhibition. Therefore, cinnamtannin B-1 may work as an allelopathic agent of D. linearis and may contribute to the establishment of pure colonies of D. linearis.

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Organ-specific-active allelopathic substance in red pine needles

Kato-Noguchi Hisashi, Fushimi Yoshiko, Kimura Fukiko, Morita Maho, Suenaga Kiyotake

Plant Growth Regulation 68 ( 2 ) 171 - 175 2012.11

Accepted, ISSN 0167-6903

An organ-specific-growth inhibitory substance was isolated from an aqueous methanol extract of red pine needles and determined by spectral data as 1-mono(16-hydroxyhexadecanoyl)glycerol. This substance inhibited root growth of cress (Lepidium sativum L.) and barnyard grass (Echinochloa crus-galli (L.) Beauv) seedlings at concentrations greater than 0.01 and 0.03 μM, respectively. The concentrations required for 50 % growth inhibition on roots of cress and barnyard grass were 0.16 and 3.4 μM, respectively. However, the inhibitory activity of the substance on shoots of cress and barnyard grass was very weak. The endogenous concentration of 1-mono(16-hydroxyhexadecanoyl)glycerol in the pine needles was 4.6 μmol kg ^-1. Two related compounds, 1-monohexadecanoylglycerol and 16-hydroxyhexadecanlic acid had no activity up to 1,000 μM on cress roots and shoots. The effectiveness of 1-mono(16-hydroxyhexadecanoyl)glycerol on root growth inhibition and the occurrence of 1-mono(16-hydroxyhexadecanoyl)glycerol in pine needles suggest the substance may play an important role in the allelopathy of red pine. Root-specific-growth-inhibition by the substance may be one of the strategies for red pine to compete with neighboring plants for nutrients and space because root growth of competitive plants may be very important for their whole plant development.

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Total synthesis and biological evaluation of auripyrones A and B

Hayakawa Ichiro, Takemura Takuma, Fukasawa Emi, Ebihara Yuta, Sato Natsuki, Nakamura Takayasu, Suenaga Kiyotake, Kigoshi Hideo

Bulletin of the Chemical Society of Japan 85 ( 10 ) 1077 - 1092 2012.10

Accepted, ISSN 0009-2673

The total synthesis of auripyrones was achieved by using a novel aldol-type reaction of γ-pyrone as a key step. From this synthetic work, we have established the stereostructure and absolute configuration of auripyrone B. Furthermore, the cytotoxicities of auripyrones against a panel of 39 human cancer cell lines (termed JFCR39) at the Japanese Foundation for Cancer Research were investigated. The patterns of the differential cytotoxicities of auripyrones were COMPARE negative, suggesting that they inhibit cancer cell proliferation through a novel mechanism.

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A potent allelopathic substance in cucumber plants and allelopathy of cucumber

Kato-Noguchi Hisashi, Le Thi Ho, Sasaki Hiroaki, Suenaga Kiyotake

Acta Physiologiae Plantarum 34 ( 5 ) 2045 - 2049 2012.09

Accepted, ISSN 0137-5881

A potent growth inhibitory substance was isolated from an aqueous methanol extract of cucumber (Cucumis sativus L. cv. Phung Tuong) plants and determined as (2S)-2,3-dihydro-2α-(4-hydroxy-3-methoxyphenyl)-7-methoxy-5-(1,2,3-trihydroxypropyl)benzofuran-3β-methanol (sisymbrifolin) by spectral data. Sisymbrifolin inhibited the growth of cress (Lepidium sativum) and Echinochloa crus-galli seedlings at concentrations greater than 3 μM. Concentration of sisymbrifolin in the cucumber plants was the greatest among four growth inhibitory substances, (S)-2-benzoyloxy-3-phenyl-1-propanol, 9-hydroxy-4,7-megastigmadien-9-one, (6S,7E,9S)-6,9,10-trihydroxy-4,7-megastigmadien-3-one, and sisymbrifolin found in the cucumber, whereas growth inhibitory activity of 9-hydroxy-4,7-megastigmadien-9-one against cress and E. crus-galli was the greatest. Total activities of these substances (concentration of the substance/concentration required 50 % growth inhibition) were 14. 4, 13. 2, 8. 5 and 10. 7 for (S)-2-benzoyloxy-3-phenyl-1-propanol, 9-hydroxy-4,7-megastigmadien-9-one, (6S,7E,9S)-6,9,10-trihydroxy-4,7-megastigmadien-3-one and sisymbrifolin, respectively. These total activities were about 100-fold greater than those of phenolic acids, which are often mentioned as putative allelochemicals of plants. Thus, these substances may play important roles in the allelopathy of cucumber plants through the growth inhibition of neighboring plant species.

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Fluorescent Aplyronine A: Intracellular Accumulation and Disassembly of Actin Cytoskeleton in Tumor Cells.

Masaki Kita, Kozo Yoneda, Yuichiro Hirayama, Kota Yamagishi, Yuki Saito, Yuka Sugiyama, Yoshihiro Miwa, Osamu Ohno, Maho Morita, Kiyotake Suenaga, and Hideo Kigoshi:

ChemBioChem 13 1754-1758 2012.08

Research paper (scientific journal), Joint Work, Accepted

Isolation and structures of biselyngbyasides B, C, and D from the marine cyanobacterium Lyngbya sp., and the biological activities of biselyngbyasides

Morita Maho, Ohno Osamu, Teruya Toshiaki, Yamori Takao, Inuzuka Toshiyasu, Suenaga Kiyotake

Tetrahedron 68 ( 30 ) 5984 - 5990 2012.07

Accepted, ISSN 0040-4020

Bioassay-guided fractionation of the marine cyanobacterium Lyngbya sp. led to the isolation of biselyngbyasides B (3), C (4), and D (5), novel analogs of biselyngbyaside (1) and biselyngbyolide A (2). The gross structures of 3-5 were determined by NMR spectral analyses, and their stereochemistries were established based on NOESY spectra and CD data. Biselyngbyasides (1-3) showed growth-inhibitory activity and apoptosis-inducing activity against both HeLa S ₃ cells and HL60 cells. The fura-2 method revealed that biselyngbyasides (1-3) increased the cytosolic Ca ²⁺ concentration in HeLa S ₃ cells.

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Isolation of allelopathic substance from Piper sarmentosum Roxb

Piyatida Pukclai, Suenaga Kiyotake, Ohno Osamu, Kato-Noguchi Hisashi

Allelopathy Journal 30 ( 1 ) 93 - 102 2012.07

Accepted, ISSN 0971-4693

Allelopathic activity of Piper sarmentosum Roxb. was determined and a potent growth inhibitory substance was isolated. The aqueous methanol extracts of P. sarmentosum inhibited the growth of 6-test plant species [cress (Lepidium sativum L.), lettuce (Lactuca sativa L.), alfalfa (Medicago sativa L.), timothy (Phleum pretense L.), Italian ryegrass (Lolium multiflorum Lam.) and crabgrass (Digitaria sanguinalis L.)] to various degrees in a dose-dependent manner. The active substance 3-phenylpropionic acid was purified from the aqueous methanol extract of P. sarmentosum and identified by ¹H-, ¹³C-NMR and MS. The threshold of 3-phenylpropionic acid for growth inhibition was 1 μM. The concentrations required for 50% growth inhibition of cress and lettuce were 1.2-9.3 μM and the concentrations required for 50% growth inhibition of timothy and Italian ryegrass were 4.7-51.8 μM. The endogenous concentration of 3-phenylpropionic acid in P. sarmentosum was 121 μmol/kg. Considering the endogenous level and the inhibitory activity, 3-phenylpropionic acid may work as allelopathic substance in P. sarmentosum through growth inhibition of neighbouring plant species.

Structure-activity studies on the spiroketal moiety of a simplified analogue of debromoaplysiatoxin with antiproliferative activity

Kikumori Masayuki, Yanagita Ryo C., Tokuda Harukuni, Suzuki Nobutaka, Nagai Hiroshi, Suenaga Kiyotake, Irie Kazuhiro

Journal of Medicinal Chemistry 55 ( 11 ) 5614 - 5626 2012.06

Accepted, ISSN 0022-2623

Aplog-1, a simplified analogue of tumor-promoting debromoaplysiatoxin, is antiproliferative but not tumor-promoting. Our recent study has suggested that local hydrophobicity around the spiroketal moiety is a crucial determinant for antiproliferative activity. To further clarify the structural features relevant to the activity, we synthesized two methyl derivatives of aplog-1, where a methyl group was installed at position 4 or 10 of the spiroketal moiety. 10-Methyl-aplog-1 (5) bound to the C1B domains of novel PKCs (δ, η, and θ) with subnanomolar K _i values, approximately 10-20 times stronger than aplog-1, and markedly inhibited the growth of many human cancer cell lines, while 4-methyl-aplog-1 (4) had levels of activity similar to those of aplog-1. Interestingly, 5 showed little tumor-promoting activity unlike the tumor promoter debromoaplysiatoxin. These results suggest that 5 is a potent PKC ligand without tumor-promoting activity and could be a therapeutic lead for the treatment of cancer, like bryostatins.

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Identification of two phytotoxins, blumenol A and grasshopper ketone, in the allelopathic Japanese rice variety Awaakamai

Kato-Noguchi Hisashi, Tamura Kazuya, Sasaki Hiroaki, Suenaga Kiyotake

Journal of Plant Physiology 169 ( 7 ) 682 - 685 2012.05

Accepted, ISSN 0176-1617

Aqueous methanol extracts of the traditional rice (Oryza sativa) variety Awaakamai, which is known to have the greatest allelopathic activity among Japanese traditional rice varieties, inhibited the growth of roots and shoots of cress (Lepidium sativum), lettuce (Lactuca sativa), timothy (Phleum pratense), Digitaria sanguinalis, Lolium multiflorum and Echinochloa crus-galli. Increasing the extract concentration increased the inhibition, suggesting that the extract of Awaakamai contains growth inhibitory substances. The extract of Awaakamai was purified and two main growth inhibitory substances were isolated and determined by spectral data as blumenol A and grasshopper ketone. Blumenol A and grasshopper ketone, respectively, inhibited the growth of cress shoots and roots at concentrations greater than 10 and 30 μmol/L. The concentrations required for 50% growth inhibition on cress roots and shoots were 84 and 27 μmol/L, respectively, for blumenol A, and 185 and 76 μmol/L, respectively, for grasshopper ketone. These results suggest that blumenol A and grasshopper ketone may contribute to the growth inhibitory effect of Awaakamai and may play an important role in the allelopathy of Awaakamai.

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Biselyngbyaside, isolated from marine cyanobacteria, inhibits osteoclastogenesis and induces apoptosis in mature osteoclasts

Yonezawa Takayuki, Mase Naomi, Sasaki Hiroaki, Teruya Toshiaki, Hasegawa Shin Ichi, Cha Byung Yoon, Yagasaki Kazumi, Suenaga Kiyotake, Nagai Kazuo, Woo Je Tae

Journal of Cellular Biochemistry 113 ( 2 ) 440 - 448 2012.02

Accepted, ISSN 0730-2312

The mass and function of bones depend on the maintenance of a complicated balance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. An inhibitor of osteoclast differentiation and/or function is expected to be useful for treatment of bone lytic diseases such as osteoporosis, rheumatoid arthritis, and tumor metastasis into bone. Biselyngbyaside is a recently isolated macrolide compound from marine cyanobacteria Lyngbya sp. that shows wide-spectrum cytotoxicity toward human tumor cell lines. In this study, we investigated the effects of biselyngbyaside on osteoclast differentiation and function. Biselyngbyaside inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis in mouse monocytic RAW264 cells and primary bone marrow-derived macrophages at a low concentration. Similarly, biselyngbyaside suppressed osteoblastic cell-mediated osteoclast differentiation in cocultures. In the RANKL-induced signaling pathway, biselyngbyaside inhibited the expression of c-Fos and NFATc1, which are important transcription factors in osteoclast differentiation. In mature osteoclasts, biselyngbyaside decreased resorption-pit formation. Biselyngbyaside also induced apoptosis accompanied by the induction of caspase-3 activation and nuclear condensation, and these effects were negated by the pancaspase inhibitor z-VAD-FMK. Taken together, the present findings indicate that biselyngbyaside suppresses bone resorption via inhibition of osteoclastogenesis and induction of apoptosis. Thus, biselyngbyaside may be useful for the prevention of bone lytic diseases.

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Biselyngbyolide A, a Novel Cytotoxic Macrolide from the Marine Cyanobacterium Lyngbya sp.

Maho Morita, Osamu Ohno, and Kiyotake Suenaga

Chem. Lett. 41 ( 2 ) 165-167 2012.02

Research paper (scientific journal), Joint Work, Accepted

Aplyronines D-H from the sea hare Aplysia kurodai

Ojika Makoto, Kigoshi Hideo, Suenaga Kiyotake, Imamura Yoshifumi, Yoshikawa Kohji, Ishigaki Takeshi, Sakakura Akira, Mutou Tsuyoshi, Yamada Kiyoyuki

Tetrahedron 68 ( 4 ) 982 - 987 2012.01

Accepted, ISSN 0040-4020

Five cytotoxic macrolides, aplyronines D-H (4-8), were isolated from the Japanese sea hare Aplysia kurodai. They are new congeners of the antitumor compound aplyronine A (1), which was previously isolated from the same organism. Their structures were determined by spectroscopic analysis (NMR and MS). The cytotoxicity of these new compounds was evaluated in comparison with that of aplyronines A-C (1-3), suggesting the importance of the 7-O-seryl ester group for mediating the potent cytotoxicity of aplyronines.

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海洋シアノバクテリア由来の医薬品リード化合物

SUENAGA Kiyotake

月刊ファインケミカル 41 ( 1 ) 45-51 2012

Research paper (scientific journal), Single Work

Secondary Metabolites with New Medicinal Functions from Marine Organisms

Ohno Osamu, Suenaga Kiyotake, Uemura Daisuke

Advances in Food and Nutrition Research 65 185 - 193 2012

Accepted, ISSN 1043-4526

We have focused on the identification of natural key compounds that possess biologically and medicinally intriguing functions. Some of bioactive naturally occurring compounds isolated from marine organisms were found to possess unique biological activities. Halichlorine from the marine sponge Halichondria okadai was shown to inhibit the activity of nuclear factor-κB in endothelial cells and block L-type Ca ²⁺ channels. Thus, it may have therapeutic potentials for diseases such as atherosclerosis and hypertension.

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Synthesis and structure-activity studies of simplified analogues of aplysiatoxin with antiproliferative activity like bryostatin-1

Irie Kazuhiro, Kikumori Masayuki, Kamachi Hiroaki, Tanaka Keisuke, Murakami Akira, Yanagita Ryo C., Tokuda Harukuni, Suzuki Nobutaka, Nagai Hiroshi, Suenaga Kiyotake, Nakagawa Yu

Pure and Applied Chemistry 84 ( 6 ) 1341 - 1351 2012

Accepted, ISSN 0033-4545

Protein kinase C (PKC) isozymes are promising targets for anticancer therapy. Bryostatin-1 (bryo-1), a unique PKC activator with little tumor-promoting activity, is currently in clinical trials for the treatment of cancer. However, its limited availability from natural sources and its synthetic complexity have hampered studies of its mode of action and structural optimization as a therapeutic agent. The development of synthetically more accessible compounds with bryo-1-like activities is thus needed. Recently, we developed a simple and less lipophilic analogue of tumor-promoting aplysiatoxin (ATX) (aplog-1) as a promising lead for bryo-1-like anticancer drugs. Structure-activity studies suggested that local hydro -phobicity around the spiroketal moiety of aplog-1 is a crucial determinant of its antiproliferative activity. The hydrophobic analogue (12,12-dimethyl-aplog-1) displayed more potent antiproliferative activity. Moreover, it showed little tumor-promoting activity and even suppressed the tumor promotion by 12-O-tetradecanoylphorbol 13-acetate (TPA) in vivo and in vitro. Aplog-1 and bryo-1 bound selectively to novel PKC isozymes (δ, η, and θ) while tumor promoters bound to both conventional and novel PKC isozymes. These results suggest that the unique biological activities of aplog-1 and bryo-1 are ascribable in part to the ability to bind to PKCδ, but weak binding to conventional PKC isozymes might also be important.

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Halichonines A, B, and C, novel sesquiterpene alkaloids from the marine sponge Halichondria okadai Kadota

Ohno Osamu, Chiba Tatsuhiko, Todoroki Seiji, Yoshimura Hideaki, Maru Norihito, Maekawa Ken, Imagawa Hiroshi, Yamada Kaoru, Wakamiya Atsushi, Suenaga Kiyotake, Uemura Daisuke

Chemical Communications 47 ( 46 ) 12453 - 12455 2011.12

Accepted, ISSN 1359-7345

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Allelopathy of red pine: isolation and identification of an allelopathic substance in red pine needles.

Kato-Noguchi Hisashi, Fushimi Yoshiko, Tanaka Yukitoshi, Teruya Toshiaki, Suenaga Kiyotake

Plant Growth Regulation 65 ( 2 ) 299 - 304 2011.11

Accepted, ISSN 0167-6903

Since red pine (Pinus densiflora Sieb. et Zucc.) often forms sparse forest floors where herbaceous plants do not grow well, allelopathy of red pine was investigated. A growth inhibitory substance was isolated from an aqueous methanol extract of red pine needles and determined by spectral data as abscisic acid-β-d-glucopyranosyl ester (ABA-GE). This substance inhibited root and shoot growth of cress and E. crus-galli seedlings at concentrations greater than 0. 1 μM. The concentrations required for 50% growth inhibition on roots and shoots of cress were 0.23 and 0.61 μM, respectively, and those of E. crus-galli were 1. 1 and 2. 8 μM, respectively. The activity of ABA-β-d-glucosidase, which liberates free ABA from ABA-GE, in cress and E. crus-galli seedlings was 13-29 nmol mg^-1 protein min^-1. Endogenous concentration of ABA-GE in the pine needles was 4. 1-21. 5 μmol kg^-1 and the concentration in soil water of the pine forest was 2. 5 μM. The effectiveness of ABA-GE on growth inhibition and the occurrence of ABA-GE in pine needles and soil water suggest ABA-GE may play an important role in the allelopathy of red pine resulting in the formation of sparse forest floors.

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Two potent allelopathic substances in cucumber plants

Kato-Noguchi Hisashi, Le Thi Ho, Teruya Toshiaki, Suenaga Kiyotake

Scientia Horticulturae 129 ( 4 ) 894 - 897 2011.07

Accepted, ISSN 0304-4238

Since cucumber plants are mostly discarded as large waste after crop harvesting, allelopathy of cucumber plants was investigated for possible weed management options and utilization of the waste. Two potent growth inhibitory substances were isolated from an aqueous methanol extract of cucumber (Cucumis sativus L. cv. Phung Tuong) plants. These substances were determined as 9-hydroxy-4,7-megastigmadien-9-one (HMO) and (6S,7E,9S)-6,9,10-trihydroxy-4,7-megastigmadien-3-one (THMO) by the analysis of MS, ¹H NMR spectra and optical rotation. HMO inhibited the growth of cress (Lepidium sativum L.) and Echinochloa crus-galli (L.) Beauv seedlings at concentrations greater than 0.3 and 1μM, respectively. THMO inhibited the growth of cress and E. crus-galli seedlings at concentrations greater than 1 and 3μM, respectively. The concentrations required for 50% growth inhibition on roots and shoots of cress and E. crus-galli were 2.4-29.3μM for HMO and 8.1-52.2μM for THMO. The endogenous levels of HMO and THMO in cucumber plants were 31.8 and 43.5μgg^-1 dry weight, respectively. These results suggest that HMO and THMO may be the causal factors for the growth inhibitory effect of cucumber plants. Therefore, cucumber plants may be potentially useful for weed management options in an agricultural setting, such as a cover crop and soil admixture, which should be investigated further in the field.

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Cell-morphology profiling of a natural product library identifies bisebromoamide and miuraenamide A as actin filament stabilizers

Sumiya Eriko, Shimogawa Hiroki, Sasaki Hiroaki, Tsutsumi Masato, Yoshita Keņichi, Ojika Makoto, Suenaga Kiyotake, Uesugi Motonari

ACS Chemical Biology 6 ( 5 ) 425 - 431 2011.05

Accepted, ISSN 1554-8929

Natural products provide a rich source of biological tools, but elucidating their molecular targets remains challenging. Here we report a cell morphological profiling of a natural product library, which permitted the identification of bisebromoamide and miuraenamide A as actin filament stabilizers. Automated high-content image analysis showed that these two structurally distinct marine natural products induce morphological changes in HeLa cells similar to those induced by known actin-stabilizing compounds. Bisebromoamide and miuraenamide A stabilized actin filaments in vitro, and fluorescein-conjugated bisebromoamide localized specifically to actin filaments in cells. Cell morphological profiling was also used to identify actinstabilizing or -destabilizing natural products from marine sponge extracts, leading to the isolation of pectenotoxin-2 and lyngbyabellin C. Overall, the results demonstrate that high-content imaging of nuclei and cell shapes offers a sensitive and convenient method for detecting and isolating molecules that target actin.

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N,N′-diphenethylurea isolated from Okinawan ascidian Didemnum molle enhances adipocyte differentiation in 3T3-L1 cells

Choi Sun Sil, Cha Byung Yoon, Kagami Iida, Lee Young Sil, Sasaki Hiroaki, Suenaga Kiyotake, Teruya Toshiaki, Yonezawa Takayuki, Nagai Kazuo, Woo Je Tae

Journal of Antibiotics 64 ( 3 ) 277 - 280 2011.03

Accepted, ISSN 0021-8820

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Revised structure and structure-activity relationship of bisebromoamide and structure of norbisebromoamide from the marine cyanobacterium Lyngbya sp.

Sasaki Hiroaki, Teruya Toshiaki, Fukazawa Hidesuke, Suenaga Kiyotake

Tetrahedron 67 ( 5 ) 990 - 994 2011.02

Accepted, ISSN 0040-4020

Novel potent cytotoxic peptides bisebromoamide (1) and norbisebromoamide (2) have been isolated from the marine cyanobacterium Lyngbya sp. The planar structure of these peptides was elucidated through the extensive application of 1D and 2D NMR techniques. The absolute stereostructure of 1 was determined by chemical degradation followed by chiral HPLC analysis. Recently, Tao and co-workers achieved synthesis of bisebromoamide, and the configuration of thiazoline moiety was revised. We re-investigated the stereochemistry of thiazoline moiety of 1. The structure-activity relationships of bisebromoamide (1) were investigated with the use of natural and synthetic analogs. Furthermore, bisebromoamide (1) potently inhibited protein kinase: the phosphorylation of ERK in NRK cells by PDGF-stimulation was selectively inhibited by treatment with 10-0.1 μM of 1.

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Marine natural product aurilide activates the opa1-mediated apoptosis by binding to prohibitin

Sato Shin Ichi, Murata Asako, Orihara Tsubasa, Shirakawa Takashi, Suenaga Kiyotake, Kigoshi Hideo, Uesugi Motonari

Chemistry and Biology 18 ( 1 ) 131 - 139 2011.01

Accepted, ISSN 1074-5521

Aurilide is a potent cytotoxic marine natural product that induces apoptosis in cultured human cells at the picomolar to nanomolar range; however, its mechanism of action has been unknown. Results of the present study showed that aurilide selectively binds to prohibitin 1 (PHB1) in the mitochondria, activating the proteolytic processing of optic atrophy 1 (OPA1) and resulting in mitochondria-induced apoptosis. The mechanism of aurilide cytotoxicity suggests that PHB1 is an apoptosis-regulating protein amenable to modulation by small molecules. Aurilide may serve as a small-molecule tool for studies of mitochondria-induced apoptosis.

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Isolation and identification of potent allelopathic substances in a traditional bangladeshi rice cultivar kartikshail

Kato-Noguchi Hisashi, Salam Md Abdus, Suenaga Kiyotake

Plant Production Science 14 ( 2 ) 128 - 134 2011

Accepted, ISSN 1343-943X

Aqueous methanol extracts of a traditional Bangladeshi rice cultivar (Oryza sativa L. cv. Kartikshail) inhibited root and shoot growth of cress (Lepidium sativum), lettuce (Lactuca sativa), alfalfa (Medicago sativa), timothy (Phleum pratense), crabgrass (Digitaria sanguinalis), Italian ryegrass (Lolium multiflorum), barnyardgrass (Echinochloa crus-galli) and jungle rice (Echinochloa colonum). The inhibition was increased with increasing the extract concentration, which suggests that cv. Kartikshail may have growth inhibitory substances and allelopathic potential. The aqueous methanol extract of cv. Kartikshail was purified and two main inhibitory substances were isolated and identified by spectral data as 3-hydroxy-β-ionone and 9-hydroxy-4-megastigmen-3-one. The concentrations required for 50% growth inhibition on cress roots and shoots, respectively, were 4.9 and 9.5 μM for 3-hydroxy-β-ionone, and 0.54 and 0.72 μM for 9-hydroxy-4-megastigmen-3-one. The concentrations required for 50% growth inhibition on barnyardgrass roots and shoots, respectively, were 160 and 310 μM for 3-hydroxy-β-ionone, and 53 and 140 μM for 9-hydroxy-4- megastigmen-3-one. The inhibitory activity of a mixture of the two compounds was much higher than that of the sum of the two compounds, suggesting that the two compounds may act synergistically to inhibit the growth of cress and barnyardgrass. The present research suggests that 3-hydroxy-β -ionone and 9-hydroxy-4-megastigmen-3-one may be responsible for the growth inhibitory effect of cv. Kartikshail and may play important roles in the allelopathy of cv. Kartikshail. The traditional Bangladeshi rice cultivar Kartikshail may be potentially useful for weed management as a weed suppressing agent when this rice cultivar is incorporated into the soil or included in rice-based cropping systems.

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Allelopathic potential and chemical composition of rhinacanthus nasutus extracts

Piyatida Pukclai, Suenaga Kiyotake, Kato-Noguchi Hisashi

Allelopathy Journal 26 ( 2 ) 207 - 216 2010.10

Accepted, ISSN 0971-4693

Aqueous methanol extracts of Rhinacanthus nasutus (L.) Kurz inhibited the shoot and root growth of cress (Lepidum sativum L.), lettuce (Lactuca sativa L.), alfalfa (Medicago sativa L.), timothy (Phleum pratense L.), Italian ryegrass (Lolium multiflorum Lam) and crabgrass (Digitaria sanguinalis L.) at concentrations > 0.1 g dry weight equivalent extract/mL and the inhibition increased with increasing extract concentration. These results suggest that the extract of R. nasutus may possess allelopathic activity. An active substance was then isolated and determined by ¹H-, ¹³C-NMR and MS as 4-hydroxy-3-methoxybenzoic acid (vanillic acid). This is the first report of finding the vanillic acid in R. nasutus. The concentrations required for 50% growth inhibition of cress and lettuce were about 470 - 800 μM and the concentrations required for 50% growth inhibition of timothy and Italian ryegrass were 0.17 - 8.2 μM, which suggest that effectiveness of vanillic acid on timothy and Italian ryegrass was much greater than on cress and lettuce. The inhibitory activity and the occurrence of vanillic acid in R. nasutus suggest that vanillic acid may play an important role in the allelopathic properties of R. nasutus. The information obtained could be utilized in the development of bioherbicide for future weed management.

Total synthesis of auripyrones A and B and determination of the absolute configuration of auripyrone B

Hayakawa Ichiro, Takemura Takuma, Fukasawa Emi, Ebihara Yuta, Sato Natsuki, Nakamura Takayasu, Suenaga Kiyotake, Kigoshi Hideo

Angewandte Chemie - International Edition 49 ( 13 ) 2401 - 2405 2010.03

Accepted, ISSN 1433-7851

Isolation and identification of potent allelopathic substances in rattail fescue

Kato-Noguchi Hisashi, Yamamoto Madoka, Tamura Kazuya, Teruya Toshiaki, Suenaga Kiyotake, Fujii Yoshiharu

Plant Growth Regulation 60 ( 2 ) 127 - 131 2010.03

Accepted, ISSN 0167-6903

Aqueous methanol extracts of rattail fescue (Vulpia myuros) inhibited the growth of roots and shoots of cress (Lepidium sativum), lettuce (Lactuca sativa), alfalfa (Medicago sativa), timothy (Phleum pratense), Digitaria sanguinalis and Lolium multiflorum. Increasing the extract concentration increased the inhibition, suggesting that rattail fescue may have growth inhibitory substances and possess allelopathic potential. The aqueous methanol extract of rattail fescue was purified and two main inhibitory substances were isolated and identified by spectral data as (-)-3-hydroxy-β-ionone and (+)-3-oxo-α-ionol. Both substances inhibited root and shoot growth of cress at concentrations greater than 0.3 μM. The concentrations required for 50% growth inhibition on root and shoot growth of cress, lettuce, alfalfa, timothy, D. sanguinalis and L. multiflorum were 2.7-19.7 μM for (-)-3-hydroxy-β-ionone, and 2.1-34.5 μM for (+)-3-oxo-α-ionol. The concentration of (-)-3-hydroxy-β-ionone and (+)-3-oxo-α-ionol, respectively, in rattail fescue was 7.8 and 3.7 μg g^-1 fresh weight. Considering the endogenous level and the inhibitory activity, (-)-3-hydroxy-β-ionone and (+)-3-oxo-α-ionol may work as allelopathic substances in rattail fescue through the growth inhibition of neighboring plant species.

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Cytotoxic substances from two species of Japanese sea hares

Yamada Kiyoyuki, Ojika Makoto, Kigoshi Hideo, Suenaga Kiyotake

Proceedings of the Japan Academy Series B: Physical and Biological Sciences 86 ( 3 ) 176 - 189 2010.03

Accepted, ISSN 0386-2208

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Isolation and structure of koshikalide, a 14-membered macrolide from the marine cyanobacterium Lyngbya sp.

Iwasaki Arihiro, Teruya Toshiaki, Suenaga Kiyotake

Tetrahedron Letters 51 ( 6 ) 959 - 960 2010.02

Accepted, ISSN 0040-4039

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Synthesis of palau'amide and its diastereomers: Confirmation of its stereostructure

Sugiyama Hirokazu, Watanabe Atsushi, Teruya Toshiaki, Suenaga Kiyotake

Tetrahedron Letters 50 ( 52 ) 7343 - 7345 2009.12

Accepted, ISSN 0040-4039

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Isolation of C ₁₁ cyclopentenones from two didemnid species, Lissoclinum sp. and Diplosoma sp.

Ogi Takayuki, Margiastuti Palupi, Teruya Toshiaki, Taira Junsei, Suenaga Kiyotake, Ueda Katsuhiro

Marine Drugs 7 ( 4 ) 816 - 832 2009.12

Accepted, ISSN 1660-3397

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Bisebromoamide, a potent cytotoxic peptide from the marine cyanobacterium lyngbya sp.

Teruya Toshiaki, Sasaki Hiroaki, Fukazawa Hidesuke, Suenaga Kiyotake

Organic Letters 11 ( 21 ) 5062 - 5065 2009.11

Accepted, ISSN 1523-7060

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Unusual intramolecular N→O acyl group migration occurring during conjugation of (-)-DHMEQ with cysteine

Kozawa Ikuko, Kato Kuniki, Teruya Toshiaki, Suenaga Kiyotake, Umezawa Kazuo

Bioorganic and Medicinal Chemistry Letters 19 ( 18 ) 5380 - 5382 2009.09

Accepted, ISSN 0960-894X

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Synthetic studies on reidispongiolide A, an actin-depolymerizing marine macrolide: Synthesis of C11-C22 and C23-C35 segments.

Akiyama Satoshi, Toriihara Eisuke, Suzuki Kazushi, Teruya Toshiaki, Suenaga Kiyotake

Tetrahedron Letters 50 ( 35 ) 5012 - 5014 2009.09

Accepted, ISSN 0040-4039

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Biselyngbyaside, a macrolide glycoside from the marine cyanobacterium lyngbya sp.

Teruya Toshiaki, Sasaki Hiroaki, Kitamura Kazuhiro, Nakayama Takeshi, Suenaga Kiyotake

Organic Letters 11 ( 11 ) 2421 - 2424 2009.06

Accepted, ISSN 1523-7060

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Isolation and identification of a potent allelopathic substance in Bangladesh rice

Salam Md Abdus, Morokuma Masahiro, Teruya Toshiaki, Suenaga Kiyotake, Kato-Noguchi Hisashi

Plant Growth Regulation 58 ( 2 ) 137 - 140 2009.06

Accepted, ISSN 0167-6903

Aqueous methanol extracts of Bangladesh rice (Oryza sativa L. cv. BR17) inhibited the growth of roots and shoots of cress (Lepidium sativum), lettuce (Lactuca sativa), alfalfa (Medicago sativa), timothy (Phleum pratense), Digitaria sanguinalis, Echinochloa crus-galli and Echinochloa colonum. Increasing the extract concentration increased the inhibition, suggesting that the BR17 may have growth inhibitory substances and possess allelopathic potential. The aqueous methanol extract of the BR17 was purified and a main inhibitory substance was isolated and determined by spectral data as 2,9-dihydroxy-4-megastigmen-3-one. This substance inhibited root and shoot growth of cress and E. crus-galli seedlings at concentrations greater than 0.03 and 3 μM, respectively. The concentrations required for 50% growth inhibition on cress roots and shoots were 0.22 and 0.47 μM, respectively, and on E. crus-galli roots and shoots were 36 and 133 μM, respectively. These results suggest that 2,9-dihydroxy-4-megastigmen-3-one may contribute to the growth inhibitory effect of BR17 and may play an important role in the allelopathy of BR17. Thus, Bangladesh rice BR17 may be potentially useful for weed management in a field setting.

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Synthesis of actin-depolymerizing compounds

Kitamura Kazuhiro, Teruya Toshiaki, Kuroda Takeshi, Kigoshi Hideo, Suenaga Kiyotake

Bioorganic and Medicinal Chemistry Letters 19 ( 7 ) 1896 - 1898 2009.04

Accepted, ISSN 0960-894X

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Synthetic studies of mangostin derivatives with an inhibitory activity on PDGF-induced human aortic smooth cells proliferation

Nishihama Yuko, Ogamino Takahisa, Shi Wen Lei, Cha Byung Yoon, Yonezawa Takayuki, Teruya Toshiaki, Nagai Kazuo, Suenaga Kiyotake, Woo Je Tae, Nishiyama Shigeru

Heterocycles 77 ( 2 ) 759 - 765 2009.02

Accepted, ISSN 0385-5414

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Erratum to Isolation and identification of a potent allelopathic substance in Bangladesh rice (Plant Growth Regul, (2009), 58, (137-140), 10.1007/s10725-009-9360-5)

Salam Md Abdus, Morokuma Masahiro, Teruya Toshiaki, Suenaga Kiyotake, Kato-Noguchi Hisashi

Plant Growth Regulation 59 ( 2 ) 189 2009

Accepted, ISSN 0167-6903

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Aplyronine A, a potent antitumour macrolide of marine origin, and the congeners aplyronines B-H

Yamada Kiyoyuki, Ojika Makoto, Kigoshi Hideo, Suenaga Kiyotake

Natural Product Reports 26 ( 1 ) 27 - 43 2009

Accepted, ISSN 0265-0568

Aplyronines A-H are cytotoxic macrolides isolated from the sea hare Aplysia kurodai. Aplyronine A is the major constituent among the aplyronines, and this review concentrates on the results of chemical and biological research into this natural product. The isolation, determination of stereostructure and enantioselective total synthesis of the aplyronines are covered, together with discussion of their antitumour activity and structure-activity relationships, and the three-dimensional X-ray structure of the actin-aplyronine A complex.

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Hexamollamide, a hexapeptide from an Okinawan ascidian Didemnum molle

Teruya Toshiaki, Sasaki Hiroaki, Suenaga Kiyotake

Tetrahedron Letters 49 ( 36 ) 5297 - 5299 2008.09

Accepted, ISSN 0040-4039

The bioassay-guided fractionation of the cytotoxic constituents of the Okinawan ascidian Didemnum molle led to the isolation of hexamollamide (1), a hexapeptide. The gross structure and relative stereostructure of 1 were established by spectroscopic analysis including 2D NMR techniques and single-crystal X-ray diffraction analysis. The absolute stereostructure was determined by chiral HPLC analysis of acid hydrolysates of 1. Hexamollamide (1) exhibits moderate cytotoxicity against HeLa S₃ cells.

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20-N-methylpurpuramine E

Teruya Toshiaki, Iwasaki Arihiro, Suenaga Kiyotake

Bulletin of the Chemical Society of Japan 81 ( 8 ) 1026 - 1027 2008.08

Accepted, ISSN 0009-2673

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Synthesis and cytotoxicity of aurilide analogs

Suenaga Kiyotake, Kajiwara Shuri, Kuribayashi Satomi, Handa Tomohisa, Kigoshi Hideo

Bioorganic and Medicinal Chemistry Letters 18 ( 14 ) 3902 - 3905 2008.07

Accepted, ISSN 0960-894X

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An unusual iodinated 5′-deoxyxyrofuranosyl nucleoside from an okinawan ascidian, diplosoma sp. (Chemistry Letters (2008) (448-449))

Margiastuti Palupi, Ogi Takayuki, Teruya Toshiaki, Taira Junsei, Suenaga Kiyotake, Ueda Katsuhiro

Chemistry Letters 37 ( 6 ) 670 2008.06

Accepted, ISSN 0366-7022

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Allelopathy and the allelopathic activity of a phenylpropanol from cucumber plants

Le Thi Ho, Teruya Toshiaki, Suenaga Kiyotake, Van Chin Duong, Kato-Noguchi Hisashi

Plant Growth Regulation 56 ( 1 ) 1 - 5 2008.05

Accepted, ISSN 0167-6903

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An unusual iodinated 5′-deoxyxylofuranosyl nucleoside from an Okinawan Ascidian, Diplosoma sp.

Margiastuti Pulpi, Ogi Takayuki, Teruya Toshiaki, Taira Junsei, Suenaga Kiyotake, Ueda Katsuhiro

Chemistry Letters 37 ( 4 ) 448 - 449 2008.04

Accepted, ISSN 0366-7022

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Synthetic studies on mycalolide B

Kimura Tomoyuki, Kuribayashi Satomi, Sengoku Tetsuya, Matsui Keita, Ueda Shoko, Hayakawa Ichiro, Suenaga Kiyotake, Kigoshi Hideo

Chemistry Letters 36 ( 12 ) 1490 - 1491 2007.12

Accepted, ISSN 0366-7022

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Isolation and structure elucidation of a potent growth inhibitor, helian, from blue light-illuminated sunflower (Helianthus annuus) hypocotyls

Hasegawa Tsuyoshi, Togo Shigenori, Hisamatsu Yosuke, Yamada Kosumi, Suenaga Kiyotake, Sekiguchi Mitsuhiro, Shigemori Hideyuki, Hasegawa Koji

Heterocycles 71 ( 3 ) 609 - 617 2007.03

Accepted, ISSN 0385-5414

A potent growth inhibitor was isolated from blue light-illuminated sunflower (Helianthus annuus) hypocotyls and identified as 8-(β-D-glucopyranosyloxy)-3-hydroxy-1,9,14-pentadecatriene-4,6-diyne (1, designated "helian") from analysis of its ¹H and ¹³C NMR spectra, and HRFABMS. Helian 1 showed plant growth-inhibitory activity at concentrations higher than 2.6 × 10^-6 mol/L for the cress root growth test. The amount of helian was higher in the illuminated halves than in the shaded ones in phototropically stimulated sunflower hypocotyls. These results suggest that this new potent growth inhibitor, helian, may play an important role on phototropism of sunflower hypocotyls.

Synthesis and biological activity of actin-depolymerizing substances

Suenaga Kiyotake, Kigoshi Hideo

Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry 64 ( 12 ) 1273 - 1281 2006.12

Accepted, ISSN 0037-9980

Aplyronine A 1 is a potent antitumor macrolide isolated from the sea hare Aplysia kurodai. Aplyronine A interacts with actin, one of the major proteins in cytoskeleton. We achieved total synthesis of aplyronine A and its 18 analogs and investigated structure-activity relationships. Analysis of the interaction of aplyronine analogs with actin by a photoaffinity labeling method and X-ray crystal structure analysis of actin complex with aplyronine A have been carried out. These results revealed that aplyronine A binds to actin at the hydrophobic cleft between subdomains 1 and 3 of actin. The binding mode of the macrolactone part of aplyronine A was different from previously reported macrolides. In addition, the trimethylserine moiety of aplyronine A, the essential functional group for cytotoxicity against HeLa S₃ cells, was sticking out from a surface of actin-aplyronine A complex.

Synthesis and biological activity of mycalolide analogs

Suenaga Kiyotake, Kimura Tomoyuki, Kuroda Takeshi, Matsui Keita, Miya Saori, Kuribayashi Satomi, Sakakura Akira, Kigoshi Hideo

Tetrahedron 62 ( 35 ) 8278 - 8290 2006.08

Accepted, ISSN 0040-4020

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Enantioselective synthesis of aurisides A and B, cytotoxic macrolide glycosides of marine origin

Suenaga Kiyotake, Hoshino Hiroshi, Yoshii Takanori, Mori Kazunori, Sone Hiroki, Bessho Yuhki, Sakakura Akira, Hayakawa Ichiro, Yamada Kiyoyuki, Kigoshi Hideo

Tetrahedron 62 ( 33 ) 7687 - 7698 2006.08

Accepted, ISSN 0040-4020

The enantioselective synthesis of aurisides A and B, macrolide glycosides of marine origin, was achieved by a convergent approach. The C1-C9 segment 4 was prepared from (R)-pantolactone, and the C10-C17 segment 14 was synthesized from (R)-glycidyl trityl ether. The Nozaki-Hiyama-Kishi reaction between 4 and 14 and subsequent reactions gave seco acid 10, which was converted into the aglycon (3) of aurisides by construction of the 14-membered lactone and bromine-substituted conjugated diene. The glycosylation reaction of the aglycon provided aurisides A and B.

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Isotheasaponins B₁-B₃ from Camellia sinensis var. sinensis tea leaves

Kobayashi Keiko, Teruya Toshiaki, Suenaga Kiyotake, Matsui Yoko, Masuda Hideki, Kigoshi Hideo

Phytochemistry 67 ( 13 ) 1385 - 1389 2006.07

Accepted, ISSN 0031-9422

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Structure basis for antitumor effect of aplyronine A

Hirata Kunio, Muraoka Shin, Suenaga Kiyotake, Kuroda Takeshi, Kato Kenichi, Tanaka Hiroshi, Yamamoto Masaki, Takata Masaki, Yamada Kiyoyuki, Kigoshi Hideo

Journal of Molecular Biology 356 ( 4 ) 945 - 954 2006.03

Accepted, ISSN 0022-2836

Aplyronine A, isolated from the sea hare Aplysia kurodai, possesses an exceedingly potent antitumor effect in vivo and it is one of the promising candidates as an anticancer drug. This macrolide is known to depolymerize F-actin and inhibit the polymerization of actin by forming a 1:1 complex with monomeric actin. The first complex structure of actin-aplyronine A was determined via a synchrotron X-ray analysis at a 1.45 Å resolution. As expected, aplyronine A binds to a hydrophobic cleft composed of subdomains 1 and 3 of actin by intercalating its aliphatic tail part into the actin molecule as do the other reported F-actin depolymerizing agents. Unexpectedly, this complex structure shows the specific structural features around the trimethylserine moiety, revealed as an important moiety of aplyronine A for cytotoxicity against HeLa cells. Combining this result and our previous one, the moiety should strongly relate to the specific biological activity of aplyronine A; i.e. a potent antitumor effect.

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Study of the interaction between actin and antitumor substance aplyronine A with a novel fluorescent photoaffinity probe

Kuroda Takeshi, Suenaga Kiyotake, Sakakura Akira, Handa Tomohisa, Okamoto Kazuhito, Kigoshi Hideo

Bioconjugate Chemistry 17 ( 2 ) 524 - 529 2006.03

Accepted, ISSN 1043-1802

The interaction between actin and aplyronine A, a potent antitumor and actin-depolymerizing substance of marine origin, was investigated by photoaffinity labeling experiments. Photoaffinity probes consisting of a side-chain portion of aplyronine A as a ligand, a diazirine moiety as a photoaffinity group, and a fluorophore as a detecting group were synthesized. Photolabeling experiments between actin and the probe were carried out. Actin was successfully photolabeled by the fluorescent probe and visualized clearly. The present results provide the first chemical evidence for the direct interaction between actin and the side-chain portion of aplyronine A.

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Cinachyramine, the novel alkaloid possessing a hydrazone and two aminals from Cinachyrella sp.

Shimogawa Hiroki, Kuribayashi Satomi, Teruya Toshiaki, Suenaga Kiyotake, Kigoshi Hideo

Tetrahedron Letters 47 ( 9 ) 1409 - 1411 2006.02

Accepted, ISSN 0040-4039

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Growth inhibitory polyacetylenes from galls of Hedera rhombea Bean

Yamazoe Sayumi, Hasegawa Koji, Suenaga Kiyotake, Shigemori Hideyuki

Natural Product Communications 1 ( 2 ) 87 - 94 2006.02

Accepted, ISSN 1934-578X

Plant growth inhibitory polyacetylenes have been isolated from the insect galls on flower buds of Hedera rhombea Bean (Araliaceae) formed by the ivy flower bud gall midge, Asphondylia sp. (Cecidomyiidae), and their structures elucidated by spectroscopic and chemical means. The EC₅₀ values for roots/hypocotyls growth of cress (Lepidium sativum L.) seedlings were 7.0×10^-5/8.0×10^-5 M for (Z)-8-acetoxy-1,2- epoxy-3-oxoheptadeca-9-ene-4,6-diyne, 9.5×10-5/9.0×10^-5 M for (Z)-8-acetoxy-3-oxoheptadeca-1,9-diene-4,6-diyne, 2.5×10-5/5. 5×10-6 M for (Z)-8-acetoxy-1-methoxy-3-oxoheptadeca-9-ene-4,6-diyne, and 7.5×10^-5/2.0×10^-6 M for falcarindiol, respectively. On the other hand, 8-acetoxyfalcarinol exhibited lower inhibition on roots and hypocotyls growth. Among these compounds, (Z)-8-acetoxy-1-methoxy- 3-oxoheptadeca-9-ene-4,6-diyne exhibited the strongest inhibitiory effect on root growth of cress seedlings, whereas against hypocotyl growth of cress seedlings, falcarindiol showed the strongest inhibition.

Cyclohaliclonamines A-E

Teruya Toshiaki, Kobayashi Keiko, Suenaga Kiyotake, Kigoshi Hideo

Journal of Natural Products 69 ( 1 ) 135 - 137 2006.01

Accepted, ISSN 0163-3864

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Isolation of two 13-epi-neoverrucosane-type diterpenoids from a marine sponge Axinyssa tethyoides

Shimogawa Hiroki, Teruya Toshiaki, Suenaga Kiyotake, Kigoshi Hideo

Bulletin of the Chemical Society of Japan 78 ( 7 ) 1345 - 1347 2005.07

Accepted, ISSN 0009-2673

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Synthetic studies of norzoanthamine. Preparation of the diene-yne-diene precursor of an ABC-ring fragment

Irifune Taiji, Ohashi Tomohiro, Ichino Takao, Sakai Emi, Suenaga Kiyotake, Uemura Daisuke

Chemistry Letters 34 ( 7 ) 1058 - 1059 2005.07

Accepted, ISSN 0366-7022

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Biselides A-E: novel polyketides from the Okinawan ascidian Didemnidae sp.

Teruya Toshiaki, Suenaga Kiyotake, Maruyama Sakiko, Kurotaki Mineko, Kigoshi Hideo

Tetrahedron 61 ( 27 ) 6561 - 6567 2005.07

Accepted, ISSN 0040-4020

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Phormidinines A and B, novel 2-alkylpyridine alkaloids from the cyanobacterium Phormidium sp.

Teruya Toshiaki, Kobayashi Keiko, Suenaga Kiyotake, Kigoshi Hideo

Tetrahedron Letters 46 ( 23 ) 4001 - 4003 2005.06

Accepted, ISSN 0040-4039

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Formal synthesis of optically active ingenol via ring-closing olefin metathesis

Watanabe Kazushi, Suzuki Yuto, Aoki Kenta, Sakakura Akira, Suenaga Kiyotake, Kigoshi Hideo

Journal of Organic Chemistry 69 ( 23 ) 7802 - 7808 2004.11

Accepted, ISSN 0022-3263

The construction of strained carbon skeletons by ring-closing olefin metathesis (RCM) was investigated. With well-designed diene 4, RCM was found to be applicable to the formation of a highly strained inside-outside bicyclo[4.4.1]undecane skeleton of ingenol, a bioactive diterpenoid, and formal total synthesis of optically active ingenol (1) was achieved. The key features of this synthesis are construction of an A-ring by spirocyclization of the ketone with an allylic chloride unit, 26, and ring closure of a B-ring by olefin metathesis. Starting from Funk's keto ester 6, the key intermediate aldehyde 9 in Winkler's total synthesis was synthesized in eight steps in 12.5% overall yield. This strategy of direct cyclization of a strained inside-outside skeleton provided the first easy access to optically active ingenol.

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Spongiacysteine, a novel cysteine derivative from marine sponge Spongia sp.

Kobayashi Keiko, Shimogawa Hiroki, Sakakura Akira, Teruya Toshiaki, Suenaga Kiyotake, Kigoshi Hideo

Chemistry Letters 33 ( 10 ) 1262 - 1263 2004.10

Accepted, ISSN 0366-7022

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Aurilide, a cytotoxic depsipeptide from the sea hare Dolabella auricularia: isolation, structure determination, synthesis, and biological activity

Suenaga Kiyotake, Mutou Tsuyoshi, Shibata Takunobu, Itoh Takashi, Fujita Tatsuya, Takada Noboru, Hayamizu Kozue, Takagi Masaki, Irifune Taiji, Kigoshi Hideo, Yamada Kiyoyuki

Tetrahedron 60 ( 38 ) 8509 - 8527 2004.09

Accepted, ISSN 0040-4020

The bioassay-guided fractionation of the cytotoxic constituents of the Japanese sea hare Dollabella auricularia led to the isolation of aurilide (1), a 26-membered cyclodepsipeptide. The gross structure of 1 was established by spectroscopic analysis including 2D NMR techniques. The absolute stereostructure was determined by chiral HPLC analysis of acid hydrolysates of 1 and by the enantioselective synthesis of a degradation product arising from a dihydroxylated fatty acid portion. The enantioselective synthesis of 1 was achieved in 12% overall yield (16 steps) and confirmed the absolute stereostructure of 1. The cytotoxicity of 1 was evaluated using a synthetic sample, which was found to exhibit potent cytotoxicity against HeLa S ₃ cells with an IC₅₀ of 0.011 μg/mL. Further biological and pharmacological studies of 1 have been carried out by using synthetic 1. Graphical abstract.

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Biselides A and B, novel macrolides from the okinawan ascidian didemnidae sp.

Teruya Toshiaki, Shimogawa Hiroki, Suenaga Kiyotake, Kigoshi Hideo

Chemistry Letters 33 ( 9 ) 1184 - 1185 2004.09

Accepted, ISSN 0366-7022

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Total synthesis of (-)-ent-jolkinolide D

Suenaga Kiyotake, Takayanagi Yui, Yamaura Masashi, Kigoshi Hideo

Chemistry Letters 33 ( 7 ) 918 - 919 2004.07

Accepted, ISSN 0366-7022

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Synthesis and actin-depolymerizing activity of mycalolide analogs

Suenaga Kiyotake, Miya Saori, Kuroda Takeshi, Handa Tomohisa, Kanematsu Kengo, Sakakura Akira, Kigoshi Hideo

Tetrahedron Letters 45 ( 28 ) 5383 - 5386 2004.07

Accepted, ISSN 0040-4039

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Inducing substance for abalone larval metamorphosis from the crustose coralline alga Hydrolithon samoense

Suenaga Kiyotake, Hori Hidenari, Ishida Hitoshi, Nukaya Haruo, Roberts Rodney D., Tsuji Kuniro

Fisheries Science 70 ( 2 ) 342 - 344 2004.04

Accepted, ISSN 0919-9268

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Bioorganic Studies on Marine Natural Products with Bioactivity, Such as Antitumor Activity and Feeding Attractance

Suenaga Kiyotake

Bulletin of the Chemical Society of Japan 77 ( 3 ) 443 - 451 2004.03

Accepted, ISSN 0009-2673

This account describes bioorganic studies on marine natural products with bioactivity, such as antitumor activity and feeding attractance. Chemical studies on the following bioactive compounds of marine origin have been carried out: 1) feeding attractants for the starfish Acanthaster planci, 2) potent toxins from shellfish of the genus Pinna that cause food poisoning, and 3) a variety of cytotoxic and antitumor compounds from marine invertebrates including sea hares, Dolabella auricularia and Aplysia kurodai. Their isolation, structure elucidation, synthesis, and some aspects of their biological activities are summarized.

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Isolation of tribromoacetamide from an okinawan alga and biological activities of its analogs

Kigoshi Hideo, Ichino Takao, Takada Noboru, Suenaga Kiyotake, Yamada Akihiro, Yamada Kaoru, Uemura Daisuke

Chemistry Letters 33 ( 2 ) 98 - 99 2004.02

Accepted, ISSN 0366-7022

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Nakiterpiosin, a novel cytotoxic C-nor-D-homosteroid from the Okinawan sponge Terpios hoshinota

Teruya Toshiaki, Nakagawa Satoru, Koyama Tomoyuki, Suenaga Kiyotake, Kita Masaki, Uemura Daisuke

Tetrahedron Letters 44 ( 28 ) 5171 - 5173 2003.07

Accepted, ISSN 0040-4039

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Haterumaimides J and K, potent cytotoxic diterpene alkaloids from the ascidian Lissoclinum species

Uddin M. Jasim, Kokubo Susumu, Ueda Katsuhiro, Suenaga Kiyotake, Uemura Daisuke

Chemistry Letters ( 10 ) 1028 - 1029 2002.10

Accepted, ISSN 0366-7022

Hedathiosulfonic acids A and B, novel thiosulfonic acids from the deep-sea urchin Echinocardium cordatum

Kita Masaki, Watanabe Masami, Takada Noboru, Suenaga Kiyotake, Yamada Kaoru, Uemura Daisuke

Tetrahedron 58 ( 32 ) 6405 - 6412 2002.08

Accepted, ISSN 0040-4020

Hedathiosulfonic acids A and B were isolated from the deep-sea urchin Echinocardium cordatum and were determined to be novel 6-undecanethiosulfonic acids by 2D NMR, HRMS, and methylation reaction. The stereostructure of hedathiosulfonic acid A was determined by the analysis of its degradation product, a cyclic β-hydroxysulfone. Hedathiosulfonic acids exhibited acute toxicity. We carried out various model reactions of the olefinic compounds with thiosulfonic acids and proved that, as is the case with natural products, synthesized thiosulfonic acid possessing a carbon-carbon double bond was converted into β-hydroxysulfone in the presence of oxygen.

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Total synthesis of attenols A and B

Araki Keisuke, Suenaga Kiyotake, Sengoku Tetsuya, Uemura Daisuke

Tetrahedron 58 ( 10 ) 1983 - 1995 2002.03

Accepted, ISSN 0040-4020

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Cytotoxicity and actin-depolymerizing activity of aplyronine A, a potent antitumor macrolide of marine origin, and its analogs

Kigoshi Hideo, Suenaga Kiyotake, Takagi Masaki, Akao Atsushi, Kanematsu Kengo, Kamei Noriyuki, Okugawa Youko, Yamada Kiyoyuki

Tetrahedron 58 ( 6 ) 1075 - 1102 2002.02

Accepted, ISSN 0040-4020

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Terpiodiene, a Novel Tricyclic Alcohol from the Okinawan Sponge Terpios hoshinota.

Teruya Toshiaki, Nakagawa Satoru, Koyama Tomoyuki, Suenaga Kiyotake, Uemura Daisuke

Chemistry Letters ( 1 ) 38 - 39 2002.01

Accepted, ISSN 0366-7022

Arachidonic acid and α-linolenic acid, feeding attractants for the crown-of-thorns sea star Acanthaster planci, from the sea urchin Toxopneustes pileolus

Teruya Toshiaki, Suenaga Kiyotake, Koyama Tomoyuki, Nakano Yoshikatsu, Uemura Daisuke

Journal of Experimental Marine Biology and Ecology 266 ( 2 ) 123 - 134 2001.12

Accepted, ISSN 0022-0981

In the tropical zones of the Indo-Pacific Oceans, the crown-of-thorns sea star Acanthaster planci, as the predator of corals, destroys coral reefs. We recently found that viscera of the sea urchin Toxopneustes pileolus produced a feeding attractant for this sea star. Using our simple bioassay system, we isolated arachidonic acid and α-linolenic acid as feeding attractants from T. pileolus. This is the first report about the sea star A. planci being attracted to unsaturated fatty acids. Interestingly, other unsaturated fatty acids such as eicosapentaenoic acid, docosahexaenoic acid and linoleic acid showed no activity. Our preliminary experiments indicated that these attractants have an attractive effect for the sea star both in the aquarium and in the sea. We anticipated that these attractants could be used to control A. planci. In addition, we verified the existence of arachidonic acid in the coral as one of the feeding attractants.

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Auriculol, a cytotoxic oxygenated squalene from the Japanese sea hare Dolabella auricularia

Kigoshi Hideo, Itoh Takashi, Ogawa Takafumi, Ochi Kenya, Okada Mayuko, Suenaga Kiyotake, Yamada Kiyoyuki

Tetrahedron Letters 42 ( 42 ) 7461 - 7464 2001.10

Accepted, ISSN 0040-4039

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Catharsitoxins from the Chinese remedy qiung laug

Suenaga Kiyotake, Shimogawa Hiroki, Nakagawa Satoru, Uemura Daisuke

Tetrahedron Letters 42 ( 40 ) 7079 - 7081 2001.10

Accepted, ISSN 0040-4039

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Isolation and structures of hedathiosulfonic acids A and B, novel thiosulfonic acids from the deep-sea urchin Echinocardium cordatum

Takada Noboru, Watanabe Masami, Suenaga Kiyotake, Yamada Kaoru, Kita Masaki, Uemura Daisuke

Tetrahedron Letters 42 ( 37 ) 6557 - 6560 2001.09

Accepted, ISSN 0040-4039

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Haterumaimides F-I, four new cytotoxic diterpene alkaloids from an ascidian Lissoclinum species

Uddin M. J., Kokubo S., Ueda K., Suenaga K., Uemura D.

Journal of Natural Products 64 ( 9 ) 1169 - 1173 2001.09

Accepted, ISSN 0163-3864

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Zamamistatin, a significant antibacterial bromotyrosine derivative, from the Okinawan sponge Pseudoceratina purpurea

Takada Noboru, Watanabe Reiko, Suenaga Kiyotake, Yamada Kaoru, Ueda Katsuhiro, Kita Masaki, Uemura Daisuke

Tetrahedron Letters 42 ( 31 ) 5265 - 5267 2001.07

Accepted, ISSN 0040-4039

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Structural determination of pteriatoxins A, B and C, extremely potent toxins from the bivalve Pteria penguin

Takada Noboru, Umemura Naoyashi, Suenaga Kiyotake, Uemura Daisuke

Tetrahedron Letters 42 ( 20 ) 3495 - 3497 2001.05

Accepted, ISSN 0040-4039

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Pinnatoxins B and C, the most toxic components in the pinnatoxin series from the Okinawan bivalve Pinna muricata

Takada Noboru, Umemura Naoyoshi, Suenaga Kiyotake, Chou Tong, Nagatsu Akito, Haino Takeharu, Yamada Kaoru, Uemura Daisuke

Tetrahedron Letters 42 ( 20 ) 3491 - 3494 2001.05

Accepted, ISSN 0040-4039

Pinnatoxins B and C, the most toxic components in the pinnatoxin series, were successfully purified from the Okinawan bivalve Pinna muricata. Their gross structures were determined based on NMR and MS/MS spectral analyses. Their stereostructures were mainly determined by transformation reactions. Pinnatoxins B and C, C-34 epimers of each other, have an amphoteric macrocycle composed of 6,7-spiro, 5,6-bicyclo and 6,5,6-trispiro ketal rings, the same as in pinnatoxins A and D.

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Isolation and structures of hedaols A, B, and C, new bisnorditerpenes from a Japanese brown alga

Takada Noboru, Watanabe Reiko, Suenaga Kiyotake, Yamada Kaoru, Uemura Daisuke

Journal of Natural Products 64 ( 5 ) 653 - 655 2001.05

Accepted, ISSN 0163-3864

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Isolation and structures of haterumadioxins A and B, cytotoxic endoperoxides from the Okinawan sponge Plakortis lita

Takada N., Watanabe M., Yamada A., Suenaga K., Yamada K., Ueda K., Uemura D.

Journal of Natural Products 64 ( 3 ) 356 - 359 2001.03

Accepted, ISSN 0163-3864

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Enantioselective synthesis of attenols A and B

Suenaga Kiyotake, Araki Keisuke, Sengoku Tetsuya, Uemura Daisuke

Organic Letters 3 ( 4 ) 527 - 529 2001.02

Accepted, ISSN 1523-7060

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Haterumaimides A-E, five new dichlorolissoclimide-type diterpenoids from an ascidian, Lissoclinum sp.

Uddin Md Jasim, Kokubo Susumu, Suenaga Kiyotake, Ueda Katsuhiro, Uemura Daisuke

Heterocycles 54 ( 2 ) 1039 - 1047 2001.02

Accepted, ISSN 0385-5414

Kohamaic acids A and B, novel cytotoxic sesterterpenic acids, from the marine sponge Ircinia sp

Kokubo Susumu, Yogi Kentaro, Uddin Md Jasim, Inuzuka Toshiyasu, Suenaga Kiyotake, Ueda Katsuhiro, Uemura Daisuke

Chemistry Letters ( 2 ) 176 - 177 2001.02

Accepted, ISSN 0366-7022

Structures of amamistatins A and B, novel growth inhibitors of human tumor cell lines from Nocardia asteroides

Kokubo S., Suenaga K., Shinohara C., Tsuji T., Uemura D.

Tetrahedron 56 ( 35 ) 6435 - 6440 2000.08

Accepted, ISSN 0040-4020

Pinnamine, an alkaloidal marine toxin, isolated from Pinna muricata

Takada N., Iwatsuki M., Suenaga K., Uemura D.

Tetrahedron Letters 41 ( 33 ) 6425 - 6428 2000.08

Accepted, ISSN 0040-4039

Pinnamine, a novel marine alkaloid, was isolated from the Okinawan bivalve Pinna muricata. Pinnamine was determined to be an alkaloid containing a dihydropyrone ring by spectroscopic analysis. The relative stereostructure of pinnamine was determined by an analysis of coupling constants and NOE experiments; the absolute stereostructure was determined by an analysis of the circular dichroism spectrum. Pinnamine exhibited significant acute toxicity against mice. (C) 2000 Elsevier Science Ltd.

Isolation and structure of kasarin, a novel azetinone compound, isolated from a marine microorganism

Suenaga Kiyotake, Aoyama Sachiko, Xi Wang, Arimoto Hirokazu, Yamaguchi Kohji, Yamada Kaoru, Tsuji Tomoko, Yamada Akihiro, Uemura Daisuke

Heterocycles 52 ( 3 ) 1033 - 1036 2000.03

Accepted, ISSN 0385-5414

Isolation and structures of haterumalides NA, NB, NC, ND, and NE, novel macrolides from an Okinawan sponge Ircinia sp.

Takada Noboru, Sato Hiroko, Suenaga Kiyotake, Arimoto Hirokazu, Yamada Kaoru, Ueda Katsuhiro, Uemura Daisuke

Tetrahedron Letters 40 ( 34 ) 6309 - 6312 1999.08

Accepted, ISSN 0040-4039

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Structures of amamistatins A and B, novel growth inhibitors of human tumor cell lines from an actinomycete

Suenaga K., Kokubo S., Shinohara C., Tsuji T., Uemura D.

Tetrahedron Letters 40 ( 10 ) 1945 - 1948 1999.03

Accepted, ISSN 0040-4039

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Isolation and structures of attenols A and B. novel bicyclic triols from the Chinese bivalve Pinna attenuata

Takada Noboru, Suenaga Kiyotake, Yamada Kaoru, Zheng Shu Zhen, Chen Hai Sheng, Uemura Daisuke

Chemistry Letters ( 10 ) 1025 - 1026 1999

Accepted, ISSN 0366-7022

Aurilol, a cytotoxic bromotriterpene isolated from the sea hare Dolabella auricularia

Suenaga K., Shibata T., Takada N., Kigoshi H., Yamada K.

Journal of Natural Products 61 ( 4 ) 515 - 518 1998.04

Accepted, ISSN 0163-3864

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Synthesis of the aglycon of aurisides A and B, cytotoxic macrolide glycosides of marine origin

Sone Hiroki, Suenaga Kiyotake, Bessho Yuhki, Kondo Takashi, Kigoshi Hideo, Yamada Kiyoyuki

Chemistry Letters ( 1 ) 85 - 86 1998.01

Accepted, ISSN 0366-7022

Cytotoxicity and actin depolymerizing activity of aplyronine A, a potent antitumor macrolide of marine origin, and the natural and artificial analogs

Suenaga Kiyotake, Kamei Noriyuki, Okugawa Youko, Takagi Masaki, Akao Atsushi, Kigoshi Hideo, Yamada Kiyoyuki

Bioorganic and Medicinal Chemistry Letters 7 ( 3 ) 269 - 274 1997.02

Accepted, ISSN 0960-894X

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Enantioselective Synthesis of Aurilide, a Cytotoxic 26-Membered Cyclodepsipeptide of Marine Origin

Mutou Tsuyoshi, Suenaga Kiyotake, Fujita Tatsuya, Itoh Takashi, Takada Noboru, Hayamizu Kozue, Kigoshi Hideo, Yamada Kiyoyuki

Synlett 1997 ( 2 ) 199 - 201 1997.02

ISSN 0936-5214

Dolabelides C and D, cytotoxic macrolides isolated from the sea hare Dolabella auricularia

Suenaga Kiyotake, Nagoya Tomohiro, Shibata Takunobu, Kigoshi Hideo, Yamada Kiyoyuki

Journal of Natural Products 60 ( 2 ) 155 - 157 1997.02

Accepted, ISSN 0163-3864

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Isolation and stereostructure of aurilide, a novel cyclodepsipeptide from the Japanese sea hare Dolabella auricularia

Suenaga Kiyotake, Mutou Tsuyoshi, Shibata Takunobu, Itoh Takashi, Kigoshi Hideo, Yamada Kiyoyuki

Tetrahedron Letters 37 ( 37 ) 6771 - 6774 1996.09

Accepted, ISSN 0040-4039

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Aplyronine A, a potent antitumor substance of marine origin, aplyronines B and C, and artificial analogues

Kigoshi Hideo, Suenaga Kiyotake, Mutou Tsuyoshi, Ishigaki Takeshi, Atsumi Toshiyuki, Ishiwata Hiroyuki, Sakakura Akira, Ogawa Takeshi, Ojika Makoto, Yamada Kiyoyuki

Journal of Organic Chemistry 61 ( 16 ) 5326 - 5351 1996.08

Accepted, ISSN 0022-3263

The enantioselective total synthesis of aplyronine A (1), a potent antitumor substance of marine origin, was achieved by a convergent approach. Three segments 4, 5, and 6, corresponding to the C5-C11, C21-C27, and C28-C34 portions of aplyronine A (1), were prepared using the Evans aldol reaction and the Sharpless epoxidation as key steps. The coupling reaction of 4 with iodide 7 followed by Julia olefination with sulfone 8 gave the C5-C20 segment 9, while the Julia coupling reaction between segments 5 and 6 provided the C21-C34 segment 10. Julia olefination between segments 9 and 10 and the subsequent four-carbon homologation reaction led to seco acid 83, which was converted into aplyronine A (1) by Yamaguchi lactonization followed by the introduction of two amino acids. The use of the [(3,4-dimethoxybenzyl)oxy]methyl group as a protecting group for the hydroxyl at C29 was crucial for this synthesis. The enantioselective synthesis of two natural congeners, aplyronines B (2) and C (3), was also carried out using the intermediates for the synthesis of 1, which determined the absolute stereostructures of 2 and 3 unambiguously. To study the structure-cytotoxicity relationships of aplyronines, artificial analogues of 1 were synthesized and their cytotoxicities were evaluated: the trimethylserine moiety, two hydroxyl groups, and the side chain portion in 1 turned out to be important in the potent cytotoxicity shown by 1. Biological studies with aplyronine A (1) showed that 1 inhibited polymerization of G-actin to F-actin and depolymerized F-actin to G-actin.

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Auripyrones A and B, cytotoxic polypropionates from the sea hare Dolabella auricularia

Suenaga Kiyotake, Kigoshi Hideo, Yamada Kiyoyuki

Tetrahedron Letters 37 ( 29 ) 5151 - 5154 1996.07

Accepted, ISSN 0040-4039

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Absolute stereochemistry and synthesis of aplyronines B and C, the congeners of aplyronine A, a potent antitumor substance of marine origin

Suenaga Kiyotake, Ishigaki Takeshi, Sakakura Akira, Kigoshi Hideo, Yamada Kiyoyuki

Tetrahedron Letters 36 ( 28 ) 5053 - 5056 1995.07

Accepted, ISSN 0040-4039

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Total synthesis of aplyronine A, a potent antitumor substance of marine origin

Kigoshi Hideo, Ojika Makoto, Ishigaki Takeshi, Suenaga Kiyotake, Mutou Tsuyoshi, Sakakura Akira, Ogawa Takeshi, Yamada Kiyoyuki

Journal of the American Chemical Society 116 ( 16 ) 7443 - 7444 1994.08

Accepted, ISSN 0002-7863

Synthetic Studies on Aplyronine A, a Potent Antitumor Substance of Marine Origin

Kigoshi Hideo, Ojika Makoto, Suenaga Kiyotake, Mutou Tsuyoshi, Hirano Junko, Sakakura Akira, Ogawa Takeshi, Nisiwaki Masanori, Yamada Kiyoyuki

Tetrahedron Letters 35 ( 8 ) 1247 - 1250 1994.02

Accepted, ISSN 0040-4039

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