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Papers - Arai, Midori

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Isolation and evaluation of cardenolides from Lansium domesticum as Notch inhibitors.

Anna Tsuchiya, Yoshinori Makita, Takashi Koyano, Thaworn Kowithayakorn, Masami Ishibashi, Midori A Arai

Journal of natural medicines (Journal of Natural Medicines) 74 ( 4 ) 758 - 766 2020.09

Accepted, ISSN 13403443

Since Notch signaling plays important roles in cell proliferation and differentiation, aberrant activation of this signaling contributes to cancer progression. In neural stem cells, Notch signaling inhibits differentiation by activating HES1 expression. Therefore, Notch signaling inhibitors may be candidates for new anticancer drugs or have applications in neural regenerative medicine. In this study, six naturally occurring Notch inhibitors were isolated from the methanol (MeOH) extract of Lansium domesticum using our novel cell-based assay. Hongherin (2), a cardiac glycoside, demonstrated potent Notch inhibitory activity with an IC50 of 0.62 μM and was found to be cytotoxic in HPB-ALL human T cell acute lymphoblastic leukemia cells. Hongherin (2) also induced the differentiation of C17.2 neural stem cells to neurons, causing a 65% increase in differentiation compared to the control. Mechanistically, hongherin (2) reduced the amount of Notch1 (full length) and mastermind-like protein (MAML). This indicates that hongherin (2) inhibits Notch signaling through a dual mechanism involving the reduction of both Notch1 and MAML protein levels.

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Cadinane sesquiterpenoids isolated from Santalum album using a screening program for Wnt signal inhibitory activity

Tomoyuki Sato, Midori A. Arai, Yixizhuoma, Yasumasa Hara, Takashi Koyano, Thaworn Kowithayakorn, Masami Ishibashi

Journal of Natural Medicines (Journal of Natural Medicines) 74 ( 2 ) 476 - 481 2020.03

Accepted, ISSN 13403443

© 2019, The Japanese Society of Pharmacognosy. Upon screening compounds having Wnt signal inhibitory activity through evaluating TCF/β-catenin transcriptional (TOP) activity, eight cadinane sesquiterpenoids, including three new compounds (1–3), were isolated from wood extracts of Santalum album (Santalaceae). Structures of compounds 1–3 were elucidated by spectral data to have a cadinane skeleton with an aromatic ring. Of the eight compounds isolated, compound 4, identified as mansonone I, was found to be active against TOP, having an IC50 of 1.2 μM.

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Isolation of inohanalactone, a γ-butyrolactone, from Nocardia Inohanensis IFM0092T

Natsumi Kobayashi, Yasumasa Hara, Midori A. Arai, Shoko Hara, Tohru Gonoi, Takashi Yaguchi, Masami Ishibashi

Heterocycles (Heterocycles) 101 ( 1 ) 312 - 317 2020

Accepted, ISSN 03855414

© 2020 The Japan Institute of Heterocyclic Chemistry. Because research on the genus Nocardia has not progressed as compared to the extensively studied genus Streptomyces, Nocardia is considered as a useful undeveloped resource for exploring natural products. In this study, a new γ-butyrolactone derivative, named inohanalactone (1), was isolated from Nocardia inohanensis IFM0092T. Inohanalactone possesses an aliphatic side chain containing 8 carbons, a vicinal diol, and a cis double bond. Inohanalactone was produced by N. inohanensis IFM0092T in the modified Czapek-Dox medium, whereas it was not produced in other media such as Nutrient broth, Waksman, and Yeast-Malt-Glucose media.

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Identification of BMI1 promoter inhibitors from Streptomyces sp. IFM-11958

Yusuke Yokoyama, Midori A. Arai, Yasumasa Hara, Masami Ishibashi

Bioorganic and Medicinal Chemistry (Bioorganic and Medicinal Chemistry) 27 ( 13 ) 2998 - 3003 2019.07

Accepted, ISSN 09680896

© 2019 Elsevier Ltd B-cell-specific Moloney murine leukemia virus region 1 (BMI1) is a central component of polycomb repressive complex 1 (PRC1), which maintains epigenetic repression of genes expression via chromatin condensation. BMI1 overexpression downregulates the expression of tumor suppressor genes, such as p16Ink4a and PTEN. BMI1 expression is upregulated in cancer stem cells (CSCs). Therefore, inhibitors of BMI1 expression have potential as therapeutic agents for cancer. This study aimed to identify BMI1 promoter inhibitors from actinomycetes. Using a recently constructed BMI1 promoter assay, we isolated three known compounds, elaiophylin (1), 2-methylelaiophylin (2), and nocardamin (3), from Streptomyces sp. IFM-11958 that inhibited BMI1 promoter activity with IC50 values of 30 nM, 447 nM, 22 µM, respectively. Elaiophylin (1) was the most potent. Western blot and PCR analyses revealed that elaiophylin (1) inhibited BMI1 expression at the mRNA level in human prostate cancer cells (DU145). Elaiophylin (1) also inhibited the sphere-forming activity of human hepatocellular carcinoma cells (Huh7), indicating that elaiophylin (1) suppresses the self-renewal capacity of CSCs. Elaiophylin (1) is the first BMI1 promoter inhibitor isolated from actinomycete metabolites.

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Nonactic Acid Derivatives Isolated from Streptomyces werraensis IFM12104 in a Screening Program for BMI1 Promoter Inhibitory Activity

Yusuke Yokoyama, Midori A. Arai, Yasumasa Hara, Masami Ishibashi

Natural Product Communications (Natural Product Communications) 14 ( 7 ) 2019

Accepted, ISSN 1934578X

© The Author(s) 2019 Upon screening for compounds with B cell-specific Moloney murine leukemia virus region 1 (BMI1) promoter inhibitory activity, 3 nonactic acid derivatives (1-3) were isolated from Streptomyces werraensis IFM12104. Although spectral data of compound 1 were identical with those reported in literature for 4α-(3, 5-dihydroxy-heptyl)-3α-methyl-2-oxetanone (4), compound 1 was revealed to be homononactic acid by X-ray analysis. Compounds 2 and 3 were identified as bishomononactic acid and nonactic acid using spectral data. The 3 compounds 1 to 3 inhibited BMI1 promoter activities with IC50 values of 240, 160, and 180 μM, respectively.

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The Notch inhibitor cowanin accelerates nicastrin degradation

Midori A. Arai, Ryuta Akamine, Anna Tsuchiya, Tatsuro Yoneyama, Takashi Koyano, Thaworn Kowithayakorn, Masami Ishibashi

Scientific Reports (Nature Publishing Group) 8 ( 1 ) 2018.12

Accepted, ISSN 2045-2322

Aberrant activation of Notch signaling contributes to the pathogenesis of several different types of cancer, and Notch pathway inhibitors may have significant therapeutic potential. Using a unique cell-based assay system, we isolated twelve compounds, including one new natural product from Garcinia speciosa, that inhibit the Notch signaling pathway. HES1 and HES5 are target genes of the Notch cascade, and compound 2, referred to as cowanin, decreased the protein levels of HES1 and HES5 in assay cells. Furthermore, cowanin (2) showed potent cytotoxicity against human leukemic HPB-ALL cells. The Notch signaling inhibitory activity of cowanin (2) is linked to the increased degradation of nicastrin, which is one of the components of the γ-secretase complex. To the best of our knowledge, this is the first example of a compound with Notch pathway inhibitory activity mediated by nicastrin degradation.

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Coculture of a Pathogenic Actinomycete and Animal Cells to Produce Nocarjamide, a Cyclic Nonapeptide with Wnt Signal-Activating Effect

Yasumasa Hara, Midori A. Arai, Kazufumi Toume, Hyuma Masu, Tomoyuki Sato, Katsuko Komatsu, Takashi Yaguchi, Masami Ishibashi

Organic Letters (Organic Letters) 20 ( 18 ) 5831 - 5834 2018.09

Accepted, ISSN 15237060

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GLI1 Inhibitors Identified by Target Protein Oriented Natural Products Isolation (TPO-NAPI) with Hedgehog Inhibition.

Midori A Arai, Fumie Ochi, Yoshinori Makita, Tetsuhiro Chiba, Kyohei Higashi, Akiko Suganami, Yutaka Tamura, Toshihiko Toida, Atsushi Iwama, Samir K Sadhu, Firoj Ahmed, Masami Ishibashi

ACS chemical biology (ACS Chemical Biology) 13 ( 9 ) 2551 - 2559 2018.09

Accepted, ISSN 15548929

This report describes the development of a target-protein-oriented natural-products-isolation (TPO-NAPI) method for Hedgehog inhibitors and the direct GLI1 inhibitor, 5'- O-methyl-3-hydroxyflemingin A (3), which inhibited hedgehog (Hh) signal transduction and diminished characteristics of cancer stem cells. Eight natural products (including three newly described products) that directly bind to GLI1 were rapidly obtained via the TPO-NAPI method developed using GLI1 protein-immobilized beads. 5'- O-Methyl-3-hydroxyflemingin A (3) inhibited Hh signaling (IC50 7.3 μM), leading to decreasing production of the Hh target proteins BCL2, PTCH1, and BMI1. 5'- O-Methyl-3-hydroxyflemingin A (3) was cytotoxic to Hh-related cancer cells. CD experiments revealed that 5'- O-methyl-3-hydroxyflemingin A (3) directly bound GLI1 ( Kd = 7.7 μM). Moreover, 5'- O-methyl-3-hydroxyflemingin A (3) diminished cancer stem cell characters of Huh7 such as sphere formation and production of the cancer stem cell marker EpCAM. These results suggest that Hh inhibitors can efficiently suppress the activity of cancer stem cells.

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Total syntheses of schizandriside, saracoside and (±)-isolariciresinol with antioxidant activities

Mana Sampei, Midori A. Arai, Masami Ishibashi

Journal of Natural Medicines (Springer Tokyo) 72 ( 3 ) 651 - 654 2018.06

Accepted, ISSN 13403443

Lignans are widely distributed in plants and exhibit significant pharmacological effects, including anti-tumor and antioxidative activities. Here, we describe the total synthesis of schizandriside (1), a compound we previously isolated from Saraca asoca by monitoring antioxidative activity using the 1,1-diphenyl-2-picrylhydrazyl radical scavenging assay. Starting from a tandem Michael-aldol reaction, the lignan skeleton was synthesized in 6 steps, including a cyclization step. To determine the stereochemistry of 1, we synthesized the natural product (±)-isolariciresinol (18) from alcohol 17. Comparison of the spectral data showed good agreement. Glycosylation was investigated using four different glycosyl donors. Only the Koenigs–Knorr condition using silver trifluoromethanesulfonate with 1,1,3,3-tetramethylurea provided the glycosylated product. Deprotection and purification using reverse-phase high-performance liquid chromatography gave schizandriside (1) and its diastereomer saracoside (2). Synthesized 1, 2 and 18 showed antioxidant activity with IC50 = 34.4, 28.8, 53.0 μM, respectively.

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The Notch Inhibitors Isolated from Nerium indicum

Midori A. Arai, Ryuta Akamine, Narumi Hayashi, Takashi Koyano, Thaworn Kowithayakorn, Masami Ishibashi

Journal of Natural Products (American Chemical Society) 81 ( 5 ) 1235 - 1240 2018.05

Accepted, ISSN 01633864

Notch signaling plays a crucial role in differentiation and cell maintenance, but once aberrantly activated, it contributes to cancer progression. Notch inhibitors were isolated from plant extracts and tested using an originally constructed cell-based assay system. We isolated eight compounds from Nerium indicum that showed inhibition of the Notch signaling pathway. HES1 and HES5 are target genes of the Notch signaling pathway, and oleandrin (1) decreased the protein levels of HES1 and HES5 in assay cells. Oleandrin (1) showed potent cytotoxicity against HPB-ALL cells and decreased HES1 and the Notch intracellular domain in these cells. The main mechanism of action of 1 appears to be inhibition of Notch signaling by acceleration of Notch intracellular domain degradation.

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New Flavanol Dimers from the Bark of Celtis tetrandra and Their TRAIL Resistance-Overcoming Activity

Seephonkai Prapairat, Ishikawa Ryusho, Arai Midori A, Kowithayakorn Thaworn, Koyano Takashi, Ishibashi Masami

NATURAL PRODUCT COMMUNICATIONS (Natural Product Communications) 13 ( 4 ) 427 - 430 2018.04

Accepted, ISSN 1934578X

In the courses of our search for bioactive natural products on TRAIL resistance-overcoming activity, the active EtOAc extract from the bark of Celtis tetrandra was chemically investigated. The fractionation of the extract resulted in the isolation of flavanols; (+)-afzelechin (1), (-)-epiafzelechin (2), (-)-catechin (3), and two new flavanol dimers; (-)-epiafzelechin-(4α8)-(-)-catechin (4) and (-)-epiafzelechin-(4α 8)-(-)-epicatechin (5). All isolated compounds 1-5 were tested for their TRAIL resistance-overcoming activity against AGS cells at the concentrations from 5-20 µM. It is likely that the flavanol dimers 4 and 5 exhibited weak activity in the range of the concentration of 10-20 µM as compared with the standard.

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Dehydropropylpantothenamide isolated by a co-culture of Nocardia tenerifensis IFM 10554T in the presence of animal cells

Yasumasa Hara, Midori A. Arai, Kanae Sakai, Naoki Ishikawa, Tohru Gonoi, Takashi Yaguchi, Masami Ishibashi

Journal of Natural Medicines (Journal of Natural Medicines) 72 ( 1 ) 280 - 289 2018.01

Accepted, ISSN 13403443

© 2017, The Japanese Society of Pharmacognosy and Springer Japan KK, part of Springer Nature. A new amide, named dehydropropylpantothenamide (1), was obtained by a co-culture of Nocardia tenerifensis IFM 10554T in the presence of the mouse macrophage-like cell line J774.1 in modified Czapek-Dox (mCD) medium. Compound 1 was synthesized from d-pantothenic acid calcium salt in 6 steps. The absolute configuration of natural compound 1 was determined by comparisons of the optical rotation and CD spectra of synthetic 1. In the present study, a new method for producing secondary metabolites was demonstrated using a “co-culture” in which the genus Nocardia was cultured in the presence of an animal cell line.

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Isolation of Resistomycin from a Terrestrial Actinomycete with TRAIL Resistance-overcoming Activity

Liu Xuefeidan, Arai Midori A, Toume Kazufumi, Ishibashi Masami

NATURAL PRODUCT COMMUNICATIONS (Natural Product Communications) 13 ( 1 ) 65 - 66 2018.01

Accepted, ISSN 1934578X

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) potently induces apoptosis in most cancer cells, but not in normal cells, and, thus, has attracted intense interest as a promising antitumor agent. Activity-guided fractionation of the culture broth of the actinomycete CKK1172 strain led to the isolation of the antibiotic resistomycin (1) using human gastric adenocarcinoma AGS cells. Compound 1 exhibited TRAIL resistance-overcoming activity at 2 μM with 38% more inhibition than a treatment with 1 alone (without TRAIL) in TRAIL-resistant AGS cells.

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Isolation of nabscessin C from nocardia abscessus IFM 10029T and A study on biosynthetic pathway for nabscessins

Shoko Hara, Yasumasa Hara, Midori A. Arai, Yoko Kusuya, Hiroki Takahashi, Takashi Yaguchi, Masami Ishibashi

Chemical and Pharmaceutical Bulletin (Chemical and Pharmaceutical Bulletin) 66 ( 10 ) 976 - 982 2018

Accepted, ISSN 00092363

© 2018 The Pharmaceutical Society of Japan A new aminocyclitol derivative, designated nabscessin C (1), was isolated from Nocardia abscessus IFM 10029T. Nabcessin C is an isomer of nabscessins A (2) and B (3) with different positioning of the acyl group. Absolute configuration of nabscessin A was determined by conversion into the 2-deoxy-scyllo-inosamine pentaacetyl derivative (4) by hydrolysis and acetylation of 2. The biosynthetic pathway of nabscessins is proposed based on gene expression analysis.

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Synthesis and Evaluation of Fuligocandin B Derivatives with Activity for Overcoming TRAIL Resistance

Arai Midori A, Masuda Ayaka, Suganami Akiko, Tamura Yutaka, Ishibashi Masami

CHEMICAL & PHARMACEUTICAL BULLETIN (Chemical and Pharmaceutical Bulletin) 66 ( 8 ) 810 - 817 2018

Accepted, ISSN 00092363

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling pathway induces apoptosis in cancer cells but not in normal cells. Therefore, this pathway has attracted attention regarding possible clinical treatment of cancer. However, many cancer cells demonstrate TRAIL resistance. To overcome this problem, small molecules that sensitize cancer cells to TRAIL are desired. Heterocyclic derivatives of the natural product, fuligocandin B (2), with activity for overcoming TRAIL resistance were synthesized, and their activity was evaluated. Of the synthetic molecules, the quinoline derivative (10g) showed potent activity against TRAIL-resistant gastric adenocarcinoma cells. After a docking study of the target protein valosin-containing protein, 7'-amino fuligocandin B (10m) was designed and synthesized. Compound 10m also showed good activity for overcoming TRAIL resistance. 10m produced a 49.7% difference in viability with TRAIL at 30 µM compared to without TRAIL. This activity was better than that of fuligocandin B (2).

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Boesenberols I-K, new isopimarane diterpenes from Boesenbergia pandurata with TRAIL-resistance overcoming activity

Utpal K. Karmakar, Midori A. Arai, Takashi Koyano, Thaworn Kowithayakorn, Masami Ishibashi

TETRAHEDRON LETTERS (PERGAMON-ELSEVIER SCIENCE LTD) 58 ( 40 ) 3838 - 3841 2017.10

Accepted, ISSN 0040-4039

TRAIL is a promising anticancer agent due to its unique ability to kill tumor cells selectively without harming non-malignant cells. However, some cancer cells are reported to be TRAIL-resistant. Searching potent TRAIL agonist to overcome resistance is an important strategy for its successful use as an anticancer agent. As a part of our continuous research on natural inhibitors, activity-guided fractionation of the MeOH extract of Boesenbergia pandurata rhizomes afforded three (1-3) new isopimarane diterpenes, boesenberols I-K, together with two (4-5) known compounds. The structures of these new compounds were elucidated using HRESIMS, IR, 1D and 2D NMR spectroscopy. All compounds showed TRAIL-resistance overcoming activity. (C) 2017 Elsevier Ltd. All rights reserved.

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

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

JOURNAL OF NATURAL PRODUCTS (AMER CHEMICAL SOC) 80 ( 9 ) 2453 - 2461 2017.09

Accepted, ISSN 0163-3864

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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Efficient Synthesis of Heterocyclic Flavonoids with Hedgehog Signal Inhibitory Activity

Midori A. Arai, Takao Utsumi, Natsuki Yanase, Teruhisa Fujimatsu, Masami Ishibashi

CHEMICAL & PHARMACEUTICAL BULLETIN (PHARMACEUTICAL SOC JAPAN) 65 ( 8 ) 784 - 795 2017.08

Accepted, ISSN 0009-2363

The hedgehog (Hh) signaling pathway performs important roles in embryonic development and cellular proliferation and differentiation. However, in many cancer cells Hh signaling is aberrantly activated, which has provided a strong impetus for the development of Hh pathway inhibitors. To address this, we synthesized a series of heterocyclic flavonoids and evaluated their Hh signaling inhibitory activity on cancer cell lines using our cell-based assay system. Of the synthetic flavonoids, compounds 4a and g showed good inhibitory activity (IC50 was 16.8 and 21.8 mu m, respectively), and were cytotoxic toward human pancreatic (PANC1) and prostate (DU145) cancer cells in which Hh signaling was activated. Compounds 4a and g had moderate selectivity against PANC1 cells. Western blotting analyses revealed that PTCH and GLI1 expression was reduced after treatment with these compounds. Overall, these synthetic flavonoids represent promising new additions to our expanding panel of Hh pathway inhibitors, and with further development these molecules may ultimately be considered for clinical use.

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Germacranolides from Enhydra fluctuans with TRAIL-resistance Abrogating Activity

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

NATURAL PRODUCT COMMUNICATIONS (NATURAL PRODUCTS INC) 12 ( 8 ) 1169 - 1170 2017.08

Accepted, ISSN 1934-578X

TRAIL selectively kills cancer cells without harming most normal cells. However, TRAIL resistance is a major problem for its therapeutic use. Developing a strategy to overcome resistance is crucial for the successful use of TRAIL as an antitumor agent. In our screening program of natural products that can abrogate TRAIL resistance, four germacranolides (1-4) were isolated from the aerial parts of Enhydra fluctuans. All compounds exhibited potent TRAIL resistance overcoming activity against TRAIL-resistant human gastric adenocarcinoma (AGS) cells.

Identification of BMI1 Promoter Inhibitors from Beaumontia murtonii and Eugenia operculata

Yui Kaneta, Midori A. Arai, Naoki Ishikawa, Kazufumi Toume, Takashi Koyano, Thaworn Kowithayakorn, Tetsuhiro Chiba, Atsushi Iwama, Masami Ishibashi

JOURNAL OF NATURAL PRODUCTS (AMER CHEMICAL SOC) 80 ( 6 ) 1853 - 1859 2017.06

Accepted, ISSN 0163-3864

B-Cell-specific Moloney murine leukemia virus insertion region 1 (BMI1) is a core component of the polycomb repressive complex 1 (PRC1). Abnormal expression of BMI1 is associated with a number of human malignances and cancer stem cells (CSCs), which cause chemotherapy resistance. Therefore, small molecules that inhibit BMI1 expression are potential candidates for cancer therapy. In this study, a cell-based reporter gene assay was developed that allowed BMI1 promoter activity to be measured in 293T human embryonic kidney cells based on luciferase expression levels. Using this screening assay, the methanol-soluble extracts of Beaumontia murtonii and Eugenia operculata were selected as leads. Bioassay-guided fractionation of the extracts led to the isolation of three known cardenolides (13) and one new compound (4) from B. murtonii and two known triterpenoids (5 and 6) and one new compound (7) from E. operculata. These seven compounds inhibited BMI1 promoter activity (IC50 range 0.09323.0 mu M), and the most active compound, wallichoside (1), was further evaluated. Western blot analysis revealed that wallichoside (1) decreases BMI1 protein levels in HCT116 human colon carcinoma cells, and flow cytometry analysis showed that it significantly reduced levels of the CSC biomarker epithelial cell adhesion molecule. Wallichoside (1) also inhibited sphere formation of Huh7 human hepatocellular carcinoma cells, indicating that it diminished the self-renewal capability of CSCs.

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