研究者詳細 - 荒井　緑

論文 - 荒井　緑

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Total synthesis of agalloside, isolated from Aquilaria agallocha, by the 5-O-glycosylation of flavan

Midori A. Arai, Yumi Yamaguchi, Masami Ishibashi

ORGANIC & BIOMOLECULAR CHEMISTRY （ROYAL SOC CHEMISTRY） 15 （ 23 ） 5025 - 5032 2017年06月

査読有り, ISSN 1477-0520

Agalloside (1) is a neural stem cell differentiation activator isolated from Aquilaria agallocha by our group using Hes1 immobilized beads. We conducted the first total synthesis of agalloside (1) via the 5-O-glycosylation of flavan 25 using glycosyl fluoride 20 in the presence of BF3 center dot Et2O. Subsequent oxidation with DDQ to flavanone 2 and deprotection successively provided agalloside (1). This synthetic strategy holds promise for use in the synthesis of 5-O-glycosylated flavonoids. The synthesized agalloside (1) accelerated neural stem cell differentiation, which is a result comparable to that for the naturally occurring compound 1.

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Hes1-Binding Compounds Isolated by Target Protein Oriented Natural Products Isolation (TPO-NAPI)

Midori A. Arai, Mitsuha Tanaka, Kana Tanouchi, Naoki Ishikawa, Firoj Ahmed, Samir K. Sadhu, Masami Ishibashi

JOURNAL OF NATURAL PRODUCTS （AMER CHEMICAL SOC） 80 （ 2 ） 538 - 543 2017年02月

査読有り, ISSN 0163-3864

Hairy and enhancer of split 1 (Hes1) is a transcription factor that acts in neural stem cells to inhibit differentiation. We recently developed target protein oriented natural products isolation (TPO-NAPI) using Hes1-immobilized beads to identify activators of neural stem cells. Isomicromonolactam (1), staurosporin (2), and linarin (3) were isolated as Hes1-binding compounds using the TPO-NAPI method. Of these, compound 1 enhanced neural stem cell differentiation. Using truncated Hes1 proteins, the binding region of Hes1 for 1 was estimated to be in the C-terminal half that includes a TLE/Grg binding site. The differentiation-promoting activity of inohanamine (4) is also reported.

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ISOLATION AND EVALUATION OF HEDGEHOG INHIBITORS FROM CHRISTMAS GRASS (THEMEDA ARGUENS)

Yoneyama, Tatsuro, Arai, Midori A., Koyano, Takashi, Kowithayakorn, Thaworn, Ishibashi, Masami

HETEROCYCLES （PERGAMON-ELSEVIER SCIENCE LTD） 95 （ 1 ） 210 - 222 2017年01月

査読有り, ISSN 0385-5414

The hedgehog (Hh) signaling pathway is an important regulator of embryonic development, tissue patterning, cellular proliferation and differentiation. However, aberrant activation of the pathway is associated with tumorigenesis. In this study, the Hh signal inhibitory activity of plant extracts was measured with a cell-based assay system that targets GLI1-mediated transcription. Activity guided analysis of MeOH extracts of christmas grass (Themeda arguens) led to the isolation of four inhibitory compounds: aciculatin (1), 7-de-O-methylaciculatin (2), 8-C-beta-D-boivinopyranosylapigenin (3) and aciculatinone (4). Compound 1 strongly inhibited Hh/GLI1-mediated transcriptional activity with an IC50 value of 1.8. mu M, and disrupted the formation of the GLI1-DNA complex by EMSA. 1 and 3 were cytotoxic for human prostate (DU-145) and breast (MCF-7) cancer cells. These compounds may serve as new tools for the molecular dissection of Hh pathway activation.

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Notch Inhibitors from Calotropis gigantea That Induce Neuronal Differentiation of Neural Stem Cells

Tatsuro Yoneyama, Midori A. Arai, Ryuta Akamine, Kazune Koryudzu, Anna Tsuchiya, Samir K. Sadhu, Firoj Ahmed, Motoyuki Itoh, Ryuichi Okamoto, Masami Ishibashi

Journal of Natural Products （American Chemical Society） 80 （ 9 ） 2453 - 2461 2017年

査読有り, ISSN 1520-6025

Neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease occur due to loss of the structure and function of neurons. For the potential treatment of neurodegenerative diseases, accelerators of neuronal differentiation of neural stem cells (NSCs) have been focused on and a cell-based assay system for measuring Notch signaling pathway activity was constructed. Using this assay system, eight compounds isolated from Calotropis gigantea were identified as inhibitors of the Notch signaling pathway. Hes1 and Hes5 are target genes of the Notch signaling pathway, and compound 1, called uscharin, decreased the protein levels of Hes1 and Hes5 in assay cells and MEB5 cells (mouse NSCs). Furthermore, uscharin (1) enhanced the differentiation of MEB5 cells into neurons. The mechanism of uscharin (1) for the Notch signaling inhibitory activity would be acceleration of the degradation of the Notch intracellular domain (NICD) in the MEB5 cells.

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Valosin-containing Protein is a Target of 5 '-l FuligocandinB and Enhances TRAIL Resistance in Cancer Cells

Midori A. Arai, Shota Taguchi, Kazuhiro Komatsuzaki, Kento Uchiyama, Ayaka Masuda, Mana Sampei, Mamoru Satoh, Sayaka Kado, Masami Ishibashi

CHEMISTRYOPEN （WILEY-V C H VERLAG GMBH） 5 （ 6 ） 574 - 579 2016年12月

査読有り, ISSN 2191-1363

Fuligocandin B (2) is a novel natural product that can overcome TRAIL resistance. We synthesized enatiomerically pure fuligocandin B (2) and its derivative 5'-l fuligocandin B (4), and found that the latter had an improved biological activity against the human gastric cancer cell line, AGS. We attached a biotin linker and photoactivatable aryl diazirine group to 5'-l fuligocandin B (4), and employed a pull-down assay to identify valosin-containing protein (VCP/p97), an AAA ATPase, as a 5'-l fuligocandin B (4) target protein. Knock-down of VCP by siRNA enhanced sensitivity to TRAIL in AGS cells. In addition, 4 enhanced CHOP and DR5 protein expression, and overall intracellular levels of ubiquitinated protein. These data suggest that endoplasmic reticulum stress caused through VCP inhibition by 4 increases CHOP-mediated DR5 up-regulation, which enhances TRAIL-induced cell death in AGS cells. To the best of our knowledge, this is the first example to show a relationship between VCP and TRAIL-resistance-overcoming activity in cancer cells.

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Boesenberols, Pimarane Diterpenes with TRAIL-Resistance-Overcoming Activity from Boesenbergia pandurata

Utpal K. Karmakar, Naoki Ishikawa, Midori A. Arai, Firoj Ahmed, Takashi Koyano, Thaworn Kowithayakorn, Masami Ishibashi

JOURNAL OF NATURAL PRODUCTS （AMER CHEMICAL SOC） 79 （ 8 ） 2075 - 2082 2016年08月

査読有り, ISSN 0163-3864

TRAIL is a potent and selective inducer of apoptosis in most cancer cells while sparing normal cells, which makes it an attractive target for the development of new cancer therapies. In a screening program on natural resources with the ability to abrogate TRAIL resistance, the bioassay guided fractionation of Boesenbergia pandurata rhizomes resulted in the isolation of 17 pimarane diterpenes and a monoterpene. Among these, compounds 1-8, named boesenberols A-H, are new pimarane diterpenes. All compounds exhibited TRAIL-resistance-overcoming activity in TRAIL-resistant AGS cells. Subtoxic doses of the major compound 9 sensitized AGS cells to TRAIL-induced apoptosis by up-regulating apoptosis-inducing proteins, such as DR4, DRS, p53, Fas, CHOP, Bak, and cleaved caspases-3,-8, and -9, and down-regulating the levels of cell survival proteins, such as Bcl-2, c-FLIP, and GSK-3 beta, in TRAIL-resistant AGS cells. Furthermore, compound 9 did not decrease the viability of noncancerous (HEK293) cells at concentrations up to 30 mu M.

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Cerasoidine, a Bis-aporphine Alkaloid Isolated from Polyalthia cerasoides during Screening for Wnt Signal Inhibitors

Takumi Shono, Naoki Ishikawa, Kazufumi Toume, Midori A. Arai, Hyuma Masu, Takashi Koyano, Thaworn Kowithayakorn, Masami Ishibashi

JOURNAL OF NATURAL PRODUCTS （AMER CHEMICAL SOC） 79 （ 8 ） 2083 - 2088 2016年08月

査読有り, ISSN 0163-3864

A new bis-aporphine alkaloid, cerasoidine (1), was isolated from the root extract of Polyalthia cerasoides together with the known bis-aporphine bidebiline E (2) during screening for compounds with Wnt signal inhibitory activities. The structure of cerasoidine (1) was established by X-ray analysis and shown by chiral HPLC analyses and electronic circular dichroism to be a 57:43 mixture of R(-)- and S(+)-atropisomers. Bidebiline E (2) exhibited inhibition of transcriptional activity of TCF/beta-catenin with an IC50 value of 20.2 mu M and was also found to inhibit Wnt signaling by decreasing nuclear beta-catenin.

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Bioactive Secondary Metabolites with Unique Aromatic and Heterocyclic Structures Obtained from Terrestrial Actinomycetes Species

Mohamed S. Abdelfattah, Midori A. Arai, Masami Ishibashi

CHEMICAL & PHARMACEUTICAL BULLETIN （PHARMACEUTICAL SOC JAPAN） 64 （ 7 ） 668 - 675 2016年07月

査読有り, ISSN 0009-2363

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Constituents from Entada scandens with TRAIL-resistance Overcoming Activity

Firoj Ahmed, Kazufumi Toume, Naoki Ishikawa, Midori A. Arai, Samir K. Sadhu, Masami Ishibashi

NATURAL PRODUCT COMMUNICATIONS （NATURAL PRODUCTS INC） 11 （ 7 ） 993 - 995 2016年07月

査読有り, ISSN 1934-578X

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has emerged as a promising anticancer agent because of its ability to selectively kill tumor cells. But TRAIL-resistance is a major problem of its therapy. A search for compounds for abrogating TRAIL-resistance has, thus, become an important strategy for anticancer drug discovery. In search of bioactive natural products for overcoming TRAIL-resistance, we previously reported some compounds with TRAIL-resistance overcoming activity. Bioassay guided fractionation of Entada scandens led to the isolation of four compounds (1-4). Of the isolates, compounds 1 and 3 showed moderate TRAIL-resistance overcoming activity in TRAIL-resistant human gastric adenocarcinoma (AGS) cells.

Stereochemical Assignment and Biological Evaluation of BE-14106 Unveils the Importance of One Acetate Unit for the Antifungal Activity of Polyene Macrolactams

Kohei Fujita, Ryosuke Sugiyama, Shinichi Nishimura, Naoki Ishikawa, Midori A. Arai, Masami Ishibashi, Hideaki Kakeya

JOURNAL OF NATURAL PRODUCTS （AMER CHEMICAL SOC） 79 （ 7 ） 1877 - 1880 2016年07月

査読有り, ISSN 0163-3864

Heronamides are a class of potent antifungal metabolites produced by marine-derived actinomycetes. The number of hydroxy groups and the stereochemistry of the two hydroxylated methine carbons are important for the activity of heronamide C, whereas the effect of the hydrocarbon chains is not known. In this study, the stereochemistry and the biological activity of BE-14106, another member of the heronamide class of antibiotics, isolated from an actinomycete Actinoalloteichus cyanogriseus IFM 11549 was investigated. Spectroscopic analysis coupled with photo- and O-2-induced conversion revealed that BE-14106 and the heronamides had the same stereochemistry. BE-14106 showed potent growth inhibition against fission yeast cells with an MIC value of 0.50 mu M (0.21 mu g/mL), being 4 times less potent than heronamide C, which revealed the importance of the structure of the hydrocarbon tail for the activity.

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Calotropis giganteaからのノッチシグナル伝達経路阻害を標的とした神経幹細胞分化促進剤の探索

米山達朗, 荒井緑, 岡本隆一, Sadhu Samir K., Ahmed Firoj, 石橋正己

日本薬学会年会要旨集（(公社)日本薬学会） 136年会（ 2 ） 59 - 59 2016年03月

ISSN 0918-9823

Bioassay-Guided Isolation of Compounds from Datura stramonium with TRAIL-Resistance Overcoming Activity

Utpal K. Karmakar, Kazufumi Toume, Naoki Ishikawa, Midori A. Arai, Samir K. Sadhu, Firoj Ahmed, Masami Ishibashi

NATURAL PRODUCT COMMUNICATIONS （NATURAL PRODUCTS INC） 11 （ 2 ） 185 - 187 2016年02月

査読有り, ISSN 1934-578X

TRAIL is a potent inducer of apoptosis in most cancer cells, but not in normal cells, and therefore has deserved intense interest as a promising agent for cancer therapy. In the search for bioactive natural products for overcoming TRAIL-resistance, we previously reported a number of active compounds. In our screening program on natural resources targeting overcoming TRAIL-resistance, activity-guided fractionation of the MeOH extract of Datura stramonium leaves led to the isolation of three alkaloids - scopolamine (1), trigonelline (2), and tyramine (3). Compounds 1, 2, and 3 exhibited TRAIL-resistance overcoming activity at 50, 150, and 100 mu M, respectively in TRAIL-resistant AGS cells.

Hes1 inhibitor isolated by target protein oriented natural products isolation (TPO-NAPI) of differentiation activators of neural stem cells

Midori A. Arai, Naoki Ishikawa, Mitsuha Tanaka, Kenji Uemura, Noriko Sugimitsu, Akiko Suganami, Yutaka Tamura, Takashi Koyano, Thaworn Kowithayakorn, Masami Ishibashi

CHEMICAL SCIENCE （ROYAL SOC CHEMISTRY） 7 （ 2 ） 1514 - 1520 2016年

査読有り, ISSN 2041-6520

The Hes1 dimer inhibitor, agalloside (2), which can accelerate the differentiation of neural stem cells is described. Six natural products, including one new natural product, which bind to Hes1 were rapidly isolated by a developed "target protein oriented natural products isolation" (TPO-NAPI) method using Hes1-immobilized beads. Of the six compounds, 2 inhibited Hes1 dimer formation at both the protein-and cellular level. Neural stem cells treated with 2 differentiated to neurons with longer neurites than cells treated with varproic acid or retinoic acid. Moreover, 2 exhibited specificity for neurons. This promotion of differentiation was supported by an increase in the mRNA expression of the proneural genes, Mash1 and Ngn2, which were inhibited by Hes1.

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Synthesis of rocaglamide derivatives and evaluation of their Wnt signal inhibitory activities

Midori A. Arai, Yuuki Kofuji, Yuuki Tanaka, Natsuki Yanase, Kazuki Yamaku, Rolly G. Fuentes, Utpal Kumar Karmakar, Masami Ishibashi

ORGANIC & BIOMOLECULAR CHEMISTRY （ROYAL SOC CHEMISTRY） 14 （ 11 ） 3061 - 3068 2016年

査読有り, ISSN 1477-0520

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Hedgehog/GLI-mediated transcriptional activity inhibitors from Crinum asiaticum

Midori A. Arai, Ryuta Akamine, Samir K. Sadhu, Firoj Ahmed, Masami Ishibashi

JOURNAL OF NATURAL MEDICINES （SPRINGER JAPAN KK） 69 （ 4 ） 538 - 542 2015年10月

査読有り, ISSN 1340-3443

The inhibition of the hedgehog (Hh) signaling pathway has emerged as an attractive anti-cancer strategy. As part of our continuing search for natural inhibitors of the Hh/GLI1 signaling pathway, we isolated three alkaloids (1-3) from Crinum asiaticum. Compounds 1 and 3 showed potent Hh/GLI1-mediated transcriptional inhibitory activity and exhibited cytotoxicity against human pancreatic (PANC1) and prostate (DU145) cancer cells. Our data revealed that compounds 1 and 3 clearly inhibited the Hh signaling pathway by down-regulating the expression of GLI-related proteins (PTCH and BCL2) in DU145 cells.

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Phenolic compounds from the bark of Oroxylum indicum activate the Ngn2 promoter

Rolly G. Fuentes, Midori A. Arai, Samir K. Sadhu, Firoj Ahmed, Masami Ishibashi

JOURNAL OF NATURAL MEDICINES （SPRINGER JAPAN KK） 69 （ 4 ） 589 - 594 2015年10月

査読有り, ISSN 1340-3443

A reporter gene assay that detects neurogenin 2 (Ngn2) promoter activity was utilized to identify compounds that induce neuronal differentiation. Ngn2 is a basic helix-loop-helix transcription factor that activates transcription of pro-neural genes. Using this assay system and an activity-guided approach, seven phenolic compounds were isolated from the methanol extract of Oroxylum indicum: 1 oroxylin A, 2 chrysin, 3 hispidulin, 4 baicalein, 5 apigenin, 6 baicalin, and 7 isoverbascoside. Compounds 1 and 2 induced an estimated 2.7-fold increase in Ngn2 promoter activity, whereas 3 increased the activity by 2.5-fold. Furthermore, 1 and 2 enhanced neuronal differentiation of C17.2 cells, which are multipotent stem cells.
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Coronaridine, an iboga type alkaloid from Tabernaemontana divaricata, inhibits the Wnt signaling pathway by decreasing beta-catenin mRNA expression

Kensuke Ohishi, Kazufumi Toume, Midori A. Arai, Samir K. Sadhu, Firoj Ahmed, Masami Ishibashi

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS （PERGAMON-ELSEVIER SCIENCE LTD） 25 （ 18 ） 3937 - 3940 2015年09月

査読有り, ISSN 0960-894X

Four alkaloids, voacangine (1), isovoacangine (2), coronaridine (3), and coronaridine hydroxyindolenine (4), were isolated from the MeOH extract of Tabernaemontana divaricata aerial parts by activity-guided fractionation for Wnt signal inhibitory activity. Compounds 1-4 exhibited TCF/beta-catenin inhibitory activities with IC50 values of 11.5, 6.0, 5.8, and 7.3 mu M, respectively. Of these, coronaridine (3) decreased beta-catenin levels in SW480 colon cancer cells, while this decrease in beta-catenin was not suppressed by a co-treatment with 3 and MG132, a proteasome inhibitor. These results suggested that the decrease observed in beta-catenin levels by coronaridine (3) did not depend on a proteasomal degradation process. On the other hand, the treatment of SW480 cells with coronaridine (3) caused a decrease in beta-catenin mRNA levels. Thus, coronaridine (3) may inhibit the Wnt signaling pathway by decreasing the mRNA expression of beta-catenin. (C) 2015 Elsevier Ltd. All rights reserved.

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Hedgehog inhibitors from Withania somnifera

Yoneyama, Tatsuro, Arai, Midori A., Sadhu, Samir K., Ahmed, Firoj, Ishibashi, Masami

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS （PERGAMON-ELSEVIER SCIENCE LTD） 25 （ 17 ） 3541 - 3544 2015年09月

査読有り, ISSN 0960-894X

The hedgehog (Hh) signaling pathway performs an important role in embryonic development and in cellular proliferation and differentiation. However, aberrant activation of the Hh signaling pathway is associated with tumorigenesis. Hh signal inhibition was evaluated using a cell-based assay system that targets GLI1-mediated transcription. Activity-guided isolation of the Withania somnifera MeOH extract led to the isolation of six compounds: withaferin A (1) and its derivatives (2-6). Compounds 1 and 2 showed strong inhibition of Hh/GLI1-mediated transcriptional activity with IC50 values of 0.5 and 0.6 mu M, respectively. Compounds 1, 2, 3, and 6 were cytotoxic toward human pancreatic (PANC-1), prostate (DU145) and breast (MCF7) cancer cells. Furthermore, 1 also inhibited GLI1-DNA complex formation in EMSA. (C) 2015 Elsevier Ltd. All rights reserved.

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Calotropis giganteaからのノッチシグナル伝達経路阻害剤の探索

米山達朗, 荒井緑, 岡本隆一, Sadhu Samir K., Ahmed Firoj, 石橋正己

日本生薬学会年会講演要旨集（(一社)日本生薬学会） 62回 172 - 172 2015年08月

ISSN 0919-1992

Hedgehog inhibitors from Artocarpus communis and Hyptis suaveolens

Midori A. Arai, Kyoko Uchida, Samir K. Sadhu, Firoj Ahmed, Takashi Koyano, Thaworn Kowithayakorn, Masami Ishibashi

BIOORGANIC & MEDICINAL CHEMISTRY （PERGAMON-ELSEVIER SCIENCE LTD） 23 （ 15 ） 4150 - 4154 2015年08月

査読有り, ISSN 0968-0896

The hedgehog (Hh) signaling pathway plays crucial roles in cell maintenance and proliferation during embryonic development. Naturally occurring Hh inhibitors were isolated from Artocarpus communis and Hyptis suaveolens using our previously constructed cell-based assay system. Bioactivity guided fractionation led to the isolation of 15 compounds, including seven new compounds (4, 5, 6, 7, and 9-11). The isolated compounds showed cytotoxicity against a cancer cell line (PANC1) in which Hh signaling was abnormally activated. Several compounds (12-14; GLI1 transcriptional inhibition IC50 = 7.6, 4.7, and 4.0 mu M, respectively) inhibited Hh related protein (BCL2) expression. Moreover, compounds 1, 12, and 13 disrupted GLI1 and DNA complex formation. (C) 2015 Elsevier Ltd. All rights reserved.

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