Details of a Researcher - Suenaga, Kiyotake

Papers - Suenaga, Kiyotake

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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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