基本情報

所属

• 保健科学研究院

職名

• 助教

ORCID ID

•  https://orcid.org/0000-0003-3433-3834

J-Global ID

• 201901013638463040

研究分野

• ライフサイエンス / 薬系化学、創薬科学

担当教育組織

•  学士課程　医学部（保健学科）
•  修士課程　保健科学院
•  博士課程　保健科学院

職歴

• 2019年04月 - 現在 Dept. of Medical Laboratory Sciences, Faculty of Health Sciences Hokkaido University, Japan

研究活動情報

論文

• Inhibition of Lipid Accumulation and Oxidation in Hepatocytes by Bioactive Bean Extracts

  Dya Fita Dibwe, Emi Kitayama, Saki Oba, Nire Takeishi, Hitoshi Chiba, Shu-Ping Hui

  Antioxidants 13 5 513 - 513 2024年04月25日 

  During our search for natural resources that can inhibit lipid droplet accumulation (LDA) and potentially prevent metabolic dysfunction-associated fatty liver disease (MAFLD) and its progressive stages, such as metabolic dysfunction-associated steatohepatitis (MASH), eight bean extracts (BE1–BE8) were tested for their ability to inhibit lipid accumulation and oxidation in hepatocytes. Substantial inhibitory effects on LDA with bean extracts (BEs) BE2, BE4, BE5, and BE8 were demonstrated. An advanced lipidomic approach was used to quantify the accumulation and inhibition of intracellular triacylglycerol (TAG) and its oxidized species, TAG hydroperoxide (TGOOH), in hepatocytes under fatty acid-loading conditions. The results show that the antioxidants BE2 and BE8 are potential candidates for regulating TAG and TGOOH accumulation in fatty acid-induced lipid droplets (LDs). This study suggests that bean-based foods inhibit LDs formation by decreasing intracellular lipids and lipid hydroperoxides in the hepatocytes. The metabolic profiling of BEs revealed that BE2 and BE8 contained polyphenolic compounds. These may be potential resources for the development of functional foods and drug discovery targeting MAFLD/MASH.
• Identification of a β-Carboline Alkaloid from Chemoselectively Derived Vanilla Bean Extract and Its Prevention of Lipid Droplet Accumulation in Human Hepatocytes (HepG2)

  Dya Fita Dibwe, Nire Takeishi, Saki Oba, Akiko Sakurai, Toshihiro Sakurai, Takayuki Tsukui, Hitoshi Chiba, Shu-Ping Hui

  Molecules 28 24 8024 - 8024 2023年12月09日 

  Targeting bioactive compounds to prevent lipid droplet accumulation in the liver, we explored an antioxidative extract from vanilla bean (Vainilla planifolia) after chemo-selective derivatization through heating and acid modification. The chemical analysis of vanilla bean extract through chemoselective derivatization resulted in the identification of sixteen compounds (34–50) using LC-MS/MS analysis. A β-carboline alkaloid with a piperidine C-ring and a vanillin moiety at C-1 (34) was identified by molecular networking and diagnostic fragmentation filtering approaches. β-carboline alkaloid 34 exhibited significant inhibitory activity of lipid droplet accumulation (LDAI) in oleic acid-loaded hepatocellular carcinoma HepG2 cells. The LDAI activity was associated with both activation of lipolysis and suppression of lipogenesis in the cells. The study indicates that crude plant extracts, following chemoselective derivatization, may contain bioactive compounds that could be beneficial in preventing hepatosteatosis and could serve as a source of lead compounds for drug development. This approach may be useful to investigate other mixtures of natural products and food resources.
• New Theonellapeptolides from Indonesian Marine Sponge Theonella swinhoei as Anti-austerity Agents

  Jabal Haedar, Agustinus Uria, Subehan Lallo, Dya Fita Dibwe, Toshiyuki Wakimoto

  Marine Drugs 20 11 661 - 661 2022年10月25日 

  We reported three new members of the theonellapeptolide family from theonellapeptolide II series, namely theonellapeptolides IIb (1), IIa (2), IIc (3), and three known members—IId (4), IIe (5), and Id (6)—from Kodingarengan marine sponge Theonella swinhoei collected in Makassar, Indonesia. The structures of tridecadepsipeptides 1–3, including the absolute configurations of their amino acids, were determined by the integrated NMR and tandem MS analyses followed by Marfey’s analysis. To the best of our knowledge, 1 and 2 are the first theonellapeptolide-type compounds to have a valine residue with D configuration at residue position 6. The isolated theonellapeptolide-type compounds 1–6 showed selective cytotoxic activity against human pancreatic MIA PaCa-2 cancer cells in a nutrient-deprived medium. Among them, the most potent preferential cytotoxicity was observed in new theonellapeptolide IIc (3) and known IId (4), IIe (5), and Id (6).
• Abietane diterpenes from Abies spectabilis and their anti-pancreatic cancer activity against the MIA PaCa-2 cell line

  Nguyen Duy Phan, Ashraf M. Omar, Sijia Sun, Juthamart Maneenet, Dya Fita Dibwe, Mao Sato, Surya Kant Kalauni, Naoki Toyooka, Tsutomu Fujii, Suresh Awale

  Bioorganic and Medicinal Chemistry Letters 66 2022年06月15日 

  An ethanolic extract of the stem of Abies spectabilis exhibited strong cytotoxicity against MIA PaCa-2 human pancreatic cancer cells preferentially under nutrient-deprived conditions. Therefore, phytochemical investigation of this bioactive extract was carried out, and that led the isolation of ten compounds (1–10) including a new abietane-type diterpene (1). The structure of the new compound (1) was elucidated by combined spectroscopic techniques, including HRFABMS, NMR and quantum ECD calculation. All the isolated compounds were evaluated for their efficacy against MIA PaCa-2 human pancreatic cancer cell line by employing an anti-austerity strategy. Among the tested compounds, dehydroabietinol (5) displayed the most potent activity with a PC50 value of 6.6 μM. Dehydroabietinol (5) was also found to retard the MIA PaCa-2 cell migration under normal nutrient-rich conditions displaying its anti-metastatic potential. Investigation on the mechanism suggested that dehydroabietinol (5) is an inhibitor of the key cancer cell survival Akt/mTOR/autophagy signaling pathway.
• Food-Derived β-Carboline Alkaloids Ameliorate Lipid Droplet Accumulation in Human Hepatocytes

  Dya Fita Dibwe, Saki Oba, Nire Takeishi, Toshihiro Sakurai, Takayuki Tsukui, Hitoshi Chiba, Shu-Ping Hui

  Pharmaceuticals 15 5 578 - 578 2022年05月05日 

  Lipid droplet accumulation (LDA) in hepatocytes is the initial stage of nonalcoholic fatty liver disease (NAFLD). In the search for natural compounds for the prevention of NAFLD, a series of β-carboline alkaloid derivatives, inspired by flazin and its derivative, newly identified in Crassostrea gigas Thunberg. extracts, were examined for LDA inhibition (LDAI) activity in oleic acid-loaded hepatocytes (HepG2). Eight compounds with a piperidine or pyridine C-ring were chemically synthesized (1-8). Among them, compounds 2 and 4 (flazin) with a carboxy group at C-3 and furfuryl alcohol moiety at C-1 showed low cytotoxicity and they exhibited significant LDAI activity. Compound 2 with piperidine C-ring was identified for the first time in C. gigas extract, and ameliorated the lipid accumulation with the LDAI value of 25.4%. Active compounds 2 and 4 significantly inhibited triacylglycerol species accumulation in cells. These compounds upregulated ATGL and downregulated SREBP1, FASN, and SCD1 genes, suggesting that they activated lipolysis and suppressed lipogenesis, respectively. These results suggest that β-carboline alkaloids, especially compounds 2 and 4, might be potentially useful for preventing NAFLD.
• A new anti-austerity agent, 4 '-O-methylgrynullarin from Derris scandens induces PANC-1 human pancreatic cancer cell death under nutrition starvation via inhibition of Akt/mTOR pathway

  Sijia Sun, Dya Fita Dibwe, Min Jo Kim, Ashraf M. Omar, Nguyen Duy Phan, Haruka Fujino, Nusrin Pongterdsak, Kritsaya Chaithatwatthana, Ampai Phrutivorapongkul, Suresh Awale

  BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 40 2021年05月 

  An ethanolic extract of Derris scandens flowers showed potent preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrient-deprived condition, with a PC50 value of 0.7 mu g/mL. Phytochemical investigation of this active extract led to the isolation of four prenylated isoflavones (1-4) including a new compound named 4 '-O-methylgrynullarin (1). The structure elucidation of the new compound was achieved by HRFABMS and NMR spectroscopic analysis. The isolated compounds exhibited potent anti-austerity activity against four different human pancreatic cancer cell lines under nutrient-deprived conditions. The new compound 4 '-O-methylgrynullarin (1) was also found to inhibit PANC-1 cell migration and colony formation under nutrientrich condition. Mechanistically, compound 1 inhibited key survival proteins in the Akt/mTOR signaling pathway. Therefore, 4 '-O-methylgrynullarin (1) can be considered as a potential lead compound for the anticancer drug development based on the anti-austerity strategy.
• Anti-inflammatory effects of Morus alba Linne bark on the activation of toll-like receptors and imiquimod-induced ear edema in mice

  Lin Umeyama, Besse Hardianti, Shiori Kasahara, Dya Fita Dibwe, Suresh Awale, Satoru Yokoyama, Yoshihiro Hayakawa

  BMC COMPLEMENTARY MEDICINE AND THERAPIES 21 1 2021年04月 

  Background Morus alba L. bark has been widely used in traditional medicine for treating several inflammatory diseases, such as hypertension, diabetes mellitus and coughing; however, the molecular mechanisms underlying its anti-inflammatory effects are not well understood. Methods We examined the effects of an extract of Morus alba L. bark (MabE) on Toll-like receptor (TLR) ligand-induced activation of RAW264.7 macrophages using a luciferase reporter assay and immunoassays. For the in vivo experiment, we used an imiquimod-induced ear edema model to examine the anti-inflammatory effects of MabE. Results MabE inhibited the TLR ligand-induced activation of NF-kappa B in RAW264.7 cells without affecting their viability. Consistent with the inhibition of NF-kappa B activation, MabE also inhibited the production of IL-6 and IL-1 beta from TLR ligand-treated RAW264.7 cells. In vivo MabE treatment inhibited the ear swelling of IMQ-treated mice, in addition to the mRNA expression of IL-17A, IL-1 beta and COX-2. The increases in splenic gamma delta T cells in IMQ-treated mice and the production of IL-17A from splenocytes were significantly inhibited by MabE treatment. Conclusion Our study suggests that the anti-inflammatory effects of MabE on the activation of the macrophage cell line RAW246.7 by TLRs and IMQ-induced ear edema are through the inhibition of NF-kappa B activation and IL-17A-producing gamma delta T cells, respectively.
• Anti-Austerity Activity of Thai Medicinal Plants: Chemical Constituents and Anti-Pancreatic Cancer Activities of Kaempferia parviflora

  Sijia Sun, Min Jo Kim, Dya Fita Dibwe, Ashraf M. Omar, Sirivan Athikomkulchai, Ampai Phrutivorapongkul, Takuya Okada, Kiyoshi Tsuge, Naoki Toyooka, Suresh Awale

  PLANTS-BASEL 10 2 2021年02月 

  Human pancreatic tumor cells have an intrinsic ability to tolerate nutrition starvation and survive in the hypovascular tumor microenvironment, the phenomenon termed as "austerity". Searching for an agent that inhibits such tolerance to nutrient starvation and kills the pancreatic cancer cells preferentially in nutrient-starvation is a unique anti-austerity strategy in anti-cancer drug discovery. In this strategy, plant extracts and compounds are tested against PANC-1 human pancreatic cancer cell line under the conditions of nutrient-deprived medium (NDM) and nutrient-rich medium (DMEM), to discover the compounds that show selective cytotoxicity in NDM. Screening of twenty-five Thai indigenous medicinal plant extracts for their anti-austerity activity against the PANC-1 human pancreatic cancer cell line in nutrient deprived medium (NDM) resulted in the identification of four active plants, Derris scandens, Boesenbergia pandurata, Citrus hystrix, and Kaempferia parviflora, with PC50 values 0.5-8.9 mu g/mL. K. parviflora extract also inhibited PANC-1 cancer cell colony formation. Phytochemical investigation of K. parviflora extract led to the isolation of fourteen compounds, including two polyoxygenated cyclohexanes (1 and 2), eleven flavonoids (3-13), and beta-sitosterol (14). Stereochemical assignment of compound 1 was confirmed through X-ray analysis. All isolated compounds were tested for their preferential cytotoxicity against PANC-1 cells. Among them, 5-hydroxy-7-methoxyflavone (3) displayed the most potent activity with a PC50 value of 0.8 mu M. Mechanistically, it was found to induce apoptosis in PANC-1 cell death in NDM as evident by caspase cleavage. It was also found to inhibit PANC-1 cancer cell colony formation in DMEM. Therefore, compound 3 can be considered as a potential lead compound for the anticancer drug development based on the anti-austerity strategy.
• Highly oxygenated spiro-biflavanoids from Anneslea fragrans twigs

  Ashraf M. Omar, Sijia Sun, Min Jo Kim, Ahmed M. Tawila, Dya Fita Dibwe, Ampai Phrutivorapongkul, Naoki Toyooka, Suresh Awale

  PHYTOCHEMISTRY LETTERS 40 21 - 25 2020年12月 

  Phytochemical investigation of the ethanolic extract of Anneslea fragrans twigs resulted the isolation of two new highly-oxygenated and sterically hindered spiro-biflavanoids, named fragranols B and C (1 and 2), together with a known compound 3-epilarixinol (3). The structural elucidation was achieved by HRFABMS, NMR spectroscopic analysis, and quantum ECD calculations. A plausible biogenetic pathway of the isolated compounds is also proposed.
• A Triterpene Lactone fromCallistemon citrinusInhibits the PANC-1 Human Pancreatic Cancer Cells Viability through Suppression of Unfolded Protein Response

  Ahmed M. Tawila, Sijia Sun, Min Jo Kim, Ashraf M. Omar, Dya Fita Dibwe, Suresh Awale

  CHEMISTRY & BIODIVERSITY 17 10 2020年10月 

  Human pancreatic tumor cells such as PANC-1 are known for their ability to tolerate nutrient starvation and thrive under the hypovascular tumor microenvironment, a phenomenon termed as 'austerity'. A search of agents that preferentially inhibit the cancer cell viability under the starvation condition without toxicity in the nutrient-rich condition is a promising approach in anticancer drug discovery. In this study, a triterpene lactone, 3 beta-hydroxy-13,28-epoxyurs-11-en-28-one (ursenolide), isolated from aCallistemon citrinusextract has shown strong preferential cytotoxicity against PANC-1 cells under nutrient starvation with PC(50)value of 0.4 mu m. Ursenolide-induced rounding of PANC-1 cell morphology followed by rupture of the cell membrane leading to cell death. In a real-time cell migration study, ursenolide was found to inhibit PANC-1 cell migration significantly. Mechanistically, it inhibited GRP78 and GRP94 under the starvation condition suggesting inhibition of unfolded protein response (UPR), an adaptive process of cell survival during starvation. It also inhibited the phosphorylation of the key survival protein Akt and mTOR. Overall results suggested that ursenolide is a potential anticancer agent against pancreatic cancer.
• Chemical constituents of Callistemon citrinus from Egypt and their antiausterity activity against PANC-1 human pancreatic cancer cell line

  Ahmed M. Tawila, Sijia Sun, Min Jo Kim, Ashraf M. Omar, Dya Fita Dibwe, Jun-ya Ueda, Naoki Toyooka, Suresh Awale

  BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 30 16 2020年08月 

  Human pancreatic cancer is resistant to almost all conventional chemotherapeutic agents. It is known to proliferate aggressively within hypovascular tumor microenvironment by exhibiting remarkable tolerance to nutrition starvation, a phenomenon termed as "austerity". Search for the new agents that eliminate the tolerance of cancer cells to nutrition starvation is a promising strategy in anticancer drug discovery. In this study, two new meroterpenoids named callistrilones O and P (1 and 2) together with eight known triterpenes (3-10) were isolated from the active dichloromethane extract of Callistemon citrinus leaves. The structure elucidation of the new compounds was achieved by HRFABMS, 1D, 2D NMR, and ECD quantum calculations. All isolated compounds were tested for their preferential cytotoxicity against PANC-1 human pancreatic cancer cells. Among these, callistrilone O (1) exhibited the most potent preferential cytotoxicity with a PC50 value of 0.3 nM, the strongest activity with over 2000 times potent than the positive control arctigenin. Callistrilone O (1) induced dramatic alterations in PANC-1 cell morphology leading to cell death under nutrient-deprived conditions. Compound 1 also inhibited PANC-1 cell migration and -PANC-1 colony formation under the nutrient-rich condition.
• Thiosemicarbazone(s)-anchored water soluble mono- and bimetallic Cu(ii) complexes: enzyme-like activities, biomolecular interactions, anticancer property and real-time live cytotoxicity

  Nithya Balakrishnan, Jebiti Haribabu, Ananda Krishnan Dhanabalan, Srividya Swaminathan, Sijia Sun, Dya Fita Dibwe, Nattamai Bhuvanesh, Suresh Awale, Ramasamy Karvembu

  DALTON TRANSACTIONS 49 27 9411 - 9424 2020年07月 

  The reactions of CuCl2 center dot 2H(2)O with chromone thiosemicarbazone ligands containing a -H or -CH3 substituent on terminal N yielded monometallic Cu(ii) complexes [Cu(HL1)Cl-2] (1) and [Cu(HL2)Cl-2] (2), whereas bimetallic Cu(ii) complexes [Cu(mu-Cl)(HL3)](2)Cl-2(3), [Cu(mu-Cl)(HL4)](2)Cl-2(4) and [Cu(mu-Cl)(L5)](2)(5) were obtained when a -C2H5, -C(6)H(11)or -C6H5 substituent was present, respectively, in the ligands. The complexes were characterized using elemental analyses, UV-Vis, FT-IR, EPR, mass and TGA studies. The structures of neutral monometallic and dicationic bimetallic complexes were confirmed by single crystal X-ray diffraction, and they exhibited a distorted square pyramidal geometry around Cu(ii) ions. The catecholase-mimicking activity of complexes 1-5 was examined spectrophotometrically, and the results revealed that all the complexes except 5 had the ability to oxidize 3,5-di-tert-butylcatechol (3,5-DTBC) to 3,5-di-tert-butylquinone (3,5-DTBQ) under aerobic conditions with moderate turnover numbers. In order to find the possible complex-substrate intermediates, a mass spectrometry study was carried out for complexes 1-4 in the presence of 3,5-DTBC. The phosphatase-like activity of 1-5 was also investigated using 4-nitrophenylphosphate (4-NPP) as a model substrate. All the complexes exhibited excellent phosphatase activity in DMF-H2O medium. The complexes displayed significant biomolecular interactions and antioxidant potential. Complex 3 showed good interaction with apoptotic CASP3 protein, VEGFR2 and PIM-1 kinase receptors as revealed by a molecular docking study. Complexes (3-5) exhibited promising cytotoxicity against HeLa-cervical cancer cells with IC50 values of 2.24 (3), 2.25 (4) and 3.77 (5) mu M, respectively, and showed a two-fold higher activity than cisplatin. The active complex 3 showed complete inhibition of colony formation at 10 mu M concentration. In addition, the acridine orange (AO)/ethidium bromide (EB) staining and real-time live cell imaging results confirmed that complex 3 induced cell death in HeLa cells.
• Fragranol A: A new class of spiro-triflavanoid hybrid with an unprecedented carbon skeleton from Anneslea fragrans

  Ashraf M. Omar, Sijia Sun, Min Jo Kim, Ahmed M. Tawila, Dya Fita Dibwe, Ampai Phrutivorapongkul, Naoki Toyooka, Suresh Awale

  TETRAHEDRON LETTERS 61 29 2020年07月 

  Phytochemical investigation of Anneslea fragrans twigs resulted in the discovery of fragranol A (1), a new class of structurally challenging and sterically hindered "spiro-triflavanoid" type compound possessing an unprecedented carbon skeleton. Fragranol A (1) consists of 45 carbons having six chiral carbons, including two spiro-chiral centers. Structural elucidation of 1 was achieved by HRFABMS, 1D and 2D NMR, analysis of spatial anisotropic effects, and quantum ECD calculations. A plausible biogenetic pathway of 1 is also proposed. (C) 2020 Elsevier Ltd. All rights reserved.
• Highly Potent Antiausterity Agents from Callistemon citrinus and Their Mechanism of Action against the PANC-1 Human Pancreatic Cancer Cell Line

  Ahmed M. Tawila, Sijia Sun, Min Jo Kim, Ashraf M. Omar, Dya Fita Dibwe, Jun-ya Ueda, Naoki Toyooka, Suresh Awale

  JOURNAL OF NATURAL PRODUCTS 83 7 2221 - 2232 2020年07月 

  Human pancreatic cancer cells display remarkable tolerance to nutrition starvation that help them to survive in a hypovascular tumor microenvironment, a phenomenon known as "austerity". The elucidation of agents countering this tolerance is an established antiausterity strategy in anticancer drug discovery. In this study, a Callistemon citrinus leaf extract inhibited the viability of PANC-1 human pancreatic cancer cells preferentially under nutrient-deprived medium (NDM) with a PC50 value of 7.4 mu g/mL. Workup of this extract resulted in the isolation of three new meroterpenoids, callistrilones L-N (1-3), together with 14 known compounds (4-17). The structure elucidation of the new compounds was achieved by HRFABMS and by NMR and ECD spectroscopic analysis. The new compounds showed highly potent preferential cytotoxicity against PANC-1 cells with PC50, values ranging from 10 to 65 nM in NDM. Of these, callistrilone L (1) inhibited PANC-1 cell migration and colony formation in a normal nutrient-rich condition. Callistrilone L (1) also strongly suppressed the migration of PANC-1 cells in real time. Mechanistically, 1 was found to inhibit the Akt/mTOR and autophagy activation pathway. Callistrilone L (1) and related meroterpenoids are promising leads for anticancer drug development based on the antiausterity strategy used in this work.
• Antiausterity Activity of Secondary Metabolites from the Roots of Ferula hezarlalehzarica against the PANC-1 Human Pancreatic Cancer Cell Line

  Mostafa Alilou, Dya Fita Dibwe, Stefan Schwaiger, Mojtaba Khodami, Jakob Troppmair, Suresh Awale, Hermann Stuppner

  JOURNAL OF NATURAL PRODUCTS 83 4 1099 - 1106 2020年04月 

  Human pancreatic cancer is one of the most aggressive types of cancer, with a high mortality rate. Due to the high tolerance of such cancer cells to nutrient starvation conditions, they can survive in a hypovascular tumor microenvironment. In this study, the dichloromethane extract of the roots of Ferula hezarlalehzarica showed potent preferential cytotoxic activity with a PC50 value of 0.78 mu g/mL. Phytochemical investigation of this extract led to the isolation of 18 compounds, including one new sesquiterpenoid (6) and one new monoterpenoid (18). All isolated compounds were evaluated for their preferential cytotoxicity against PANC-1 human pancreatic cancer cells by employing an antiausterity strategy. Among them, ferutinin (2) was identified as the most active compound, with a PC50 value of 0.72 mu M. In addition, the real-time effect of ferutinin (2) and compound 6 against PANC-1 cells, exposed to a nutrient-deprived medium (NDM), showed cell shrinkage, leading to cancer cell death within a short period of exposure. Compounds 2 and 6 also inhibited colony formation of PANC-1 cells. The present study indicates that the dichloromethane extract of the roots of F. hezarlalehzarica is a rich source of bioactive compounds for targeting PANC-1 cells.
• Fragranone C: a new dihydrochalcone glucopyranoside from Anneslea fragrans twigs

  Ashraf M. Omar, Dya Fita Dibwe, Sijia Sun, Ahmed M. Tawila, Min Jo Kim, Ampai Phrutivorapongkul, Naoki Toyooka, Suresh Awale

  NATURAL PRODUCT RESEARCH 2020年04月 

  A phytochemical investigation of an ethanolic extract of Anneslea fragrans twigs collected from Thailand resulted in the discovery of a new dihydrochalcone glucopyranoside named fragranone C (1), together with six previously reported compounds. The structural elucidation of the new compound was achieved by HRFABMS, NMR spectroscopic analysis and acid hydrolysis.
• Synthesis of guggulsterone derivatives as potential anti-austerity agents against PANC-1 human pancreatic cancer cells

  Aki Kohyama, Rei Yokoyama, Dya Fita Dibwe, Sahar El-Mekkawy, Meselhy R. Meselhy, Suresh Awale, Yuji Matsuya

  Bioorganic & Medicinal Chemistry Letters 30 7 126964 - 126964 2020年04月 [査読有り][通常論文]
   

  E- and Z-guggulsterones and nine guggulsterone derivatives (GSDs) were synthesized and evaluated for their preferential cytotoxicity against human PANC-1 cell in nutrient deprived medium utilizing antiausterity strategy. Among the synthesized compounds, GSD-1 and GSD-7 showed potent cytotoxicity against PANC-1 cells under nutrient-deprived conditions in a concentration dependent manner, with a PC50 value of 1.6 mu M and 3.2 mu M, respectively. The effect of GSD-1 and GSD-7 was further evaluated in a real time using live cell imaging. Both of these compounds altered PANC-1 cell morphology, leading to cell death at sub micromolar concentration range. GSD-1 and GSD-7 also inhibited PANC-1 cell colony formation in a concentration-dependent manner. GSD-1 and GSD-7 are lead structure for the anti-austerity drug development.
• Sidechain Diversification of Grandifloracin Allows Identification of Analogues with Enhanced Anti-Austerity Activity against Human PANC-1 Pancreatic Cancer Cells

  Benjamin E. Alexander, Sijia Sun, Matthew J. Palframan, Gabriele Kociok-Kohn, Dya Fita Dibwe, Shiro Watanabe, Lorenzo Caggiano, Suresh Awale, Simon E. Lewis

  CHEMMEDCHEM 15 1 125 - 135 2020年01月 

  The natural product (+)-grandifloracin is a potent "anti-austerity" agent, able to suppress the ability of various pancreatic cancer cell lines to tolerate conditions of nutrient deprivation. Such anti-austerity agents represent a promising approach to cancer chemotherapy. Here we report the synthesis and biological evaluation of racemic analogues of grandifloracin bearing diverse sidechains, of which two show enhanced potency in comparison with the natural product. Additionally, several unexpected by-products containing modifications of the grandifloracin core were isolated, identified and similarly evaluated for biological activity.
• Chemical constituents from Artemisia vulgaris and their antiausterity activities against the PANC-1 human pancreatic cancer cell line

  Ashraf M. Omar, Dya Fita Dibwe, Ahmed M. Tawila, Sijia Sun, Min Jo Kim, Suresh Awale

  NATURAL PRODUCT RESEARCH 2019年12月 

  The 70% ethanolic extract of Artemisia vulgaris showed preferential cytotoxicity against PANC-1 human pancreatic cancer cells under a nutrient-deprived condition with PC50 12.5 mu g/mL. A phytochemical investigation of this extract yielded a new bicyclic [4:3:0] sesquiterpene named (+)-vulgaric acid (1), together with eight previously reported compounds. The structural elucidation of 1 was achieved by HRFABMS and NMR analysis. The absolute configuration of 1 was deduced by computational calculations of ECD data. All isolated compounds were tested for preferential cytotoxicity against PANC-1 cells, and apigenin (3) showed the strongest activity with PC50 30.7 mu M.
• Chemical Constituents of Anneslea fragrans and Their Antiausterity Activity against the PANC-1 Human Pancreatic Cancer Cell Line

  Ashraf M. Omar, Dya Fita Dibwe, Ahmed M. Tawila, Sijia Sun, Ampai Phrutiyorapongkul, Suresh Awale

  JOURNAL OF NATURAL PRODUCTS 82 11 3133 - 3139 2019年11月 

  An ethanolic extract of Anneslea fragrans leaves showed potent preferential cytotoxicity against PANC-1 human pancreatic cancer cells under a nutrient-deprived condition, with a PC50 value of 9.6 mu g/mL. Phytochemical investigation of this active extract led to the isolation of two new secondary metabolites, fragranones A (1) and B (2), along with 15 previously reported compounds. The structure elucidation of the new compounds was achieved by HRFABMS, acid hydrolysis, NMR, and ECD spectroscopic analysis. Fragranone A (1) is the first example of a rare natural product bearing an acetonide glucose moiety. Fragranone B (2) is representative of a rare class of natural products with a threonolactone unit linked to a chalcone through an ether linkage. The isolated compounds exhibited antiausterity activity against PANG-1 cells under nutrient-deprived conditions, and betulin (14) was found to be the most potent compound tested, with a PC50 value of 8.4 mu M. In addition, fragranone A (1) was found to suppress PANG-1 cancer cell migration in real time.
• Kami-shoyo-san improves ASD-like behaviors caused by decreasing allopregnanolone biosynthesis in an SKF mouse model of autism

  Qing-Yun Guo, Ken Ebihara, Takafumi Shimodaira, Hironori Fujiwara, Kazufumi Toume, Dya Fita Dibwe, Suresh Awale, Ryota Araki, Takeshi Yabe, Kinzo Matsumoto

  PLOS ONE 14 1 2019年01月 

  Dysfunctions in the GABAergic system are associated with the pathogenesis of autism spectrum disorder (ASD). However, the mechanisms by which GABAergic system dysfunctions induce the pathophysiology of ASD remain unclear. We previously demonstrated that a selective type I 5a-reductase inhibitor SKF105111 (SKF) induced ASD-like behaviors, such as impaired sociability-related performance and repetitive grooming behaviors, in male mice. Moreover, the effects of SKF were caused by a decrease in the endogenous levels of allopregnanolone (ALLO), a positive allosteric modulator of the GABA(A) receptor. In this study, we used SKF-treated male mice as a putative animal model of ASD and examined the effects of Kami-shoyo-san (KSS) as an experimental therapeutic strategy for ASD. KSS is a traditional Kampo formula consisting of 10 different crude drugs and has been used for the treatment of neuropsychiatric symptoms. KSS dose-dependently attenuated sociability deficits and suppressed an increase in grooming behaviors in SKF-treated mice without affecting ALLO content in the prefrontal cortex. The systemic administration of the dopamine D-1 receptor antagonist SCH23390 reversed the ameliorative effects of KSS. On the other hand, the dopamine D-2 receptor antagonist sulpiride and GABA(A) receptor antagonist bicuculline only attenuated the ameliorative effect of KSS on repetitive self-grooming behaviors. The present results indicate that KSS improves SKF-induced ASD-like behaviors by facilitating dopamine receptor-mediated mechanisms and partly by neurosteroid-independent GABA(A) receptor-mediated neurotransmission. Therefore, KSS is a potential candidate for the treatment of ASD.
• Orengedokuto and san’oshashinto improve memory deficits by inhibiting age-dependent GSK-3β activation and subsequent CRMP2 phosphorylation in senescence-accelerated prone 8 mice

  Fujiwara H, Yoshida J, Dibwe D.F, Awale S, Hoshino H, Kohama H, Arai H, Kudo Y, Matsumoto K

  J Tradit Complement Med 9 4 328 - 335 2019年 [査読有り][通常論文]
  
• Kami-shoyo-san ameliorates ASD-like behaviors by inhibiting allopregnanolone biosynthesis in the brain via dopaminergic and, in part, GABAergic mechanisms

  Guo Q.Y, Ebihara K, Shimodaira T, Fujiwara H, Toume K, Dibwe D.F, Awale S, Araki R, Yabe T, Matsumoto K

  PLoS ONE 2019年 [査読有り][通常論文]
  
• Design and synthesis of functionalized coumarins as potential anti-austerity agents that eliminates cancer cells tolerance to nutrition starvation

  Awale S, Okada T, Dibwe D.F, Maruyama T, Takahara S, Okada T, Endo S, Toyooka

  Bioorg. Med. Chem Lett 23 14 1779 - 1784 2019年 [査読有り][通常論文]
   

  Human pancreatic tumor cells have inherent ability to tolerate nutrition starvation which enables them to survive in the hypovascular tumor microenvironment. Discovery of agents that selectively inhibit the cancer cells' tolerance to nutrition starvation leading to cancer cell death is a new anti-austerity approach in anti-cancer drug discovery. A series of coumarins derivatives were synthesized and evaluated for their anti-austerity activity against PANC-1 human pancreatic cancer cell line. The compound 7-Hydroxy-2-oxo-2H-chromene-3-carboxylic acid (3-phenylpropyl) amide (2c) showed highly potent selective cytotoxicity against PANC-1 cells under nutrient-deprived conditions, with a PC50 value of 0.44 mu M, without exhibiting toxicity in normal, nutrient-rich medium. Compound 2c caused dramatic alterations in PANC-1 cell morphology, leading to cell death. The compound 2c was found to inhibit PANC-1 cell migration and colony formation in a concentration-dependent manner. The compound 2c is a lead structure for the anti-austerity drug development against pancreatic cancer.
• Chemical constituents of Thai Citrus hystrix and their antiausterity activity against the PANC-1 Human Pancreatic Cancer Cell Line

  Sun S, Phrutivorapongkul A, Dibwe D. F, Balachandran, C, Awale S

  J. Nat. Prod. 81 8 1877 - 1883 2018年08月 [査読有り][通常論文]
   

  Human pancreatic cancer cells have an extreme tolerance to nutrition starvation, enabling them to survive in a hypovascular tumor microenvironment. Searching for agents that preferentially inhibit cancer cell viability under nutrition starvation conditions is a novel antiausterity strategy in anticancer drug discovery. In the present study, a hexane extract of the peels of Citrus hystrix fruits showed preferential cytotoxicity against PANC-1 human pancreatic cancer cells using a nutrient-deprived medium. Phytochemical investigation of this bioactive extract led to the isolation of 10 coumarins (1-10) including a new furanocoumarin (1). The isolated compounds were tested for their preferential cytotoxic activity against three different human pancreatic cancer cell lines [PANC-1, MIA PaCa-2, and PSN-1]. Among these, bergamottin (7) was identified as the most active constituent. In real-time live imaging, 7 was found to induce cell shrinkage, membrane blebbing, and disintegration of organelles in PANC-1 cells. Bergamottin (7) was also found to inhibit PANC-1 cell migration and colony formation. Mechanistically, 7 inhibited key survival proteins in the Akt/mTOR signaling pathway. Bergamottin (7) and related compounds are potential antiausterity candidates for drug development against pancreatic cancer.
• Ancistroyafungines A-D, 5,8′- and 5,1′-coupled naphthylisoquinoline alkaloids from a Congolese Ancistrocladus species, with antiausterity activities against human PANC-1 pancreatic cancer cells.

  Muyisa S, Lombe B.K, Doris Feineis, Dibwe D.F, Maharaj V, Awale S. Bringmann G

  Fitoterapia 130 6 - 16 2018年 [査読有り][通常論文]
   

  Four new naphthylisoquinoline alkaloids, the 5,8'-coupled ancistroyafungines A-C (1-3) and the 5,1'-linked ancistroyafungine D (4), have been isolated from the stem bark of an as yet unidentified Ancistrocladus (Ancistrocladaceae) liana recently discovered near the village Yafunga, in the North-Central region of the Democratic Republic of the Congo. Likewise obtained were eleven analogs previously identified in related African and Asian Ancistroclodus species, exhibiting five different coupling types, viz., 5,8', 5,1', 7,1', N,6', and N,8'. All of the alkaloids are S-configured at C-3 and possess an oxygen function at C-6 in the isoquinoline portion, and, thus, belong to the subclass of "Ancistrocladaceae-type" alkaloids. This finding is geo- and chemotaxonomically remarkable, since - apart from one other Ancistrocladus species from the Central Congo Basin - only Southeast Asian and East African Ancistrocladaceae are known to exclusively produce naphthylisoquinolines with these structural features. Moreover, the alkaloid pattern of this Congolese liana clearly demarcates this plant from all other Ancistrocladus taxa that have so far been botanically described, which suggests that it might represent a new species or subspecies. The new ancistroyafungines display strong preferential cytotoxic activities towards human PANC-1 pancreatic cancer cells in nutrient-deprived medium, without showing toxicity in normal, nutrient-rich conditions.
• Ancistrolikokine E3, a 5,8'-coupled naphthylisoquinoline alkaloid, eliminates the cancer cells tolerance to nutrition starvation by inhibition of the Akt/mTOR/autophagy signaling pathway.

  Awale S, Dibwe D.F, Chandrasekar B, Shaimaa F, Doris, Kimbadi B.L, Bringmann G

  J. Nat. Prod., 81 10 2282 - 2291 2018年 [査読有り][通常論文]
   

  PANC-1 human pancreatic cancer cells are characterized by their ability to proliferate aggressively under hypovascular and hypoxic conditions in the tumor micro environment, displaying a remarkable tolerance to nutrition starvation. The antiausterity strategy is a new approach in anticancer drug discovery aiming at the identification of potent agents that inhibit preferentially the survival of tumor cells during a limited supply of nutrients and oxygen. The new 5,8' -coupled naphthyldihydroisoquinoline alkaloid ancistrolikokine E-3 (4), isolated from the Congolese liana Ancistrocladus likoko, showed potent preferential cytotoxicity against PANC-1 cells under nutrient -deprived conditions, with a PC50 value of 2.5 mu M, without exhibiting toxicity in normal, nutrient -rich medium. The compound was found to induce dramatic alterations in cell morphology, leading to cell death. Moreover, it inhibited significantly PANC-1 cell migration and colony formation in a concentration -dependent manner. This study on 4 provides the first live evidence of the effect of a naphthyldihydroisoquinoline alkaloid against PANC-1 cells in nutrient -deprived medium. Mechanistic investigations conducted suggest that compound 4 is a potent inhibitor of the activation of the Akt/mTOR pathway. Furthermore, it inhibited the expression levels of the key autophagy regulators AtgS, Atg12, Beclin-1, LC3-I, and LC3-II. The results demonstrated that ancistrolikokine E-3 (4) is a potent early -stage inhibitor of the autophagy pathway in PANC-1 human pancreatic cancer cells. Ancistrolikokine E-3 (4) and related naphthylisoquinoline alkaloids are promising potential lead compounds for anticancer drug development based on the antiausterity strategy.
• Orengedokuto and san'oshashinto improve memory deficits by inhibiting aging-dependent activation of glycogen synthase kinase-3β

  Fujiwara, H, Yoshida, J, Dibwe, D.F, Awale, S, Hoshino, H, Kohama, H, Araki, H, Kudo, M, Matsumto, K

  Journal of Traditional and Complementary Medecine 9 4 328 - 335 2018年 [査読有り][通常論文]
   

  Background and aim: The aging-dependent activation of glycogen synthase kinase-3b (GSK-3b) has been suggested to be important in the onset of dementia. To discover novel therapeutic Kampo medicines for dementia, we examined the effects of orengedokuto (OGT(sic)) and san'oshashinto (SST(sic)) on memory deficits and GSK-3 beta activity in senescence-accelerated prone mice (SAMP8). Experimental procedure: The object recognition test (ORT) and conditioned fear memory test (CFT) were employed to elucidate short-term working memory and long-term fear memory. The activity of GSK-3b and the phosphorylation of related molecules were measured using a kinase assay and Western blotting. Results and conclusion: OGT and SST attenuated memory deficits in SAMP8 in ORT, but not in CFT. In ex vivo experiments, cortical GSK-3 beta activity was significantly stronger in SAMP8 than in SAMR1. The enhanced cortical GSK-3 beta activity in SAMP8 was accompanied by a significant increase in the level of phosphorylated collapsin response mediator protein-2 ( CRMP2), an important factor that is involved in the regulation of microtubule stability. OGT and SST attenuated not only increases in cortical GSK-3 beta activity, but also the levels of phosphorylated CRMP2 in SAMP8. In vitro experiments, flavonoids contained in these kampo medicines, inhibited GSK-3 beta activity in concentration-dependent manners. These results suggest that OGT and SST prevent aging-induced short-term working memory deficits by inhibiting aging-dependent elevations in the cortical GSK-3 beta activity and subsequent CRMP2 phosphorylation. (C) 2019 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC.
• Discovery of potential antiausterity agents from the Japanese cypress Chamaecyparis obtusa

  Dya Fita Dibwe, Sijia Sun, Jun-ya Ueda, Chandrasekar Balachandran, Kinzo Matsumoto, Suresh Awale

  BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 27 21 4898 - 4903 2017年11月 [査読有り][通常論文]
   

  The chloroform extract of the Japanese cypress Chamaecyparis obtusa was found to kill PANC-1 human pancreatic cancer cells preferentially in the nutrient-deprived medium without causing toxicity in the nutrient rich condition. Phytochemical investigation on this extract led to the isolation of a new sesquiterpene (1), together with the six sesquiterpenes (2-7) and a lignan (8). The isolated compounds were tested for their preferential cytotoxicity activity against five different human pancreatic cancer cell lines [PANC-1, MIA PaCa2, CAPAN-1, PSN-1, and KLM-1] by utilizing an antiausterity strategy. Among them, a-cadinol (2) was identified as the most active constituent. alpha-Cadinol (2) was found to inhibit the activation of Akt/mTOR pathway, and the hyperactivation of autophagy leading to preferential PANC-1 cell death during nutrient-starvation. (C) 2017 Elsevier Ltd. All rights reserved.
• Decrease in endogenous brain allopregnanolone induces autism spectrum disorder (ASD)-like behavior in mice: A novel animal model of ASD

  Ken Ebihara, Hironori Fujiwara, Suresh Awale, Dya Fita Dibwe, Ryota Araki, Takeshi Yabe, Kinzo Matsumoto

  BEHAVIOURAL BRAIN RESEARCH 334 6 - 15 2017年09月 [査読有り][通常論文]
   

  Autism spectrum disorder (ASD) is a neurodevelopmental disorder with core symptoms of social impairments and restrictive repetitive behaviors. Recent evidence has implicated a dysfunction in the GABAergic system in the pathophysiology of ASD. We investigated the role of endogenous allopregnanolone (ALLO), a neurosteroidal positive allosteric modulator of GABA(A) receptors, in the regulation of ASD-like behavior in male mice using SICF105111 (SKF), an inhibitor of type I and type II 5 alpha-reductase, a rate-limiting enzyme of ALLO biosynthesis. SKF impaired sociability-related performance, as analyzed by three different tests; i.e., the 3-chamber test and social interaction in the open field and resident-intruder tests, without affecting olfactory function elucidated by the buried food test. SKF also induced repetitive grooming behavior without affecting anxiety-like behavior. SKF had no effect on short-term spatial working memory or long-term fear memory, but enhanced latent learning ability in male mice. SKF-induced ASD-like behavior in male mice was abolished by the systemic administration of ALLO (1 mg/kg, i.p.) and methylphenidate (MPH: 2.5 mg/kg, i.p.), a dopamine transporter inhibitor. The effects of SKF on brain ALLO contents in male mice were reversed by ALLO, but not MPH. On the other hand, SKF failed to induce ASD-like behavior or a decline in brain ALLO contents in female mice. These results suggest that ALLO regulates episodes of ASD-like behavior by positively modulating the function of GABAA receptors linked to the dopaminergic system. Moreover, a sex-dependently induced decrease in brain ALLO contents may provide an animal model to study the main features of ASD.
• Syntheses of benzophenone-xanthone hybrid polyketides and their antibacterial activities

  Takeshi Kodama, Takuya Ito, Dya Fita Dibwe, So-Yeun Woo, Hiroyuki Morita

  BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 27 11 2397 - 2400 2017年06月 [査読有り][通常論文]
   

  Muchimangins are benzophenone-xanthone hybrid polyketides produced by Securidaca longepedunculata. However, their biological activities have not been fully investigated, since they are minor constituents in this plant. To evaluate the possibility of muchimangins as antibacterial agent candidates, five muchimangin analogs were synthesized from 2,4,5-trimethoxydiphenyl methanol and the corresponding xanthones, by utilizing p-toluenesulfonic acid monohydrate for the Bronsted acid-catalysis. The antibacterial assays against Gram-positive bacteria, Staphylococcus aureus and Bacillus subtilis, and Gram-negative bacteria, Klebsiella pneumoniae and Escherichia coli, revealed that the muchimangin analogs (+/-)-1,3,6,8-tetrahydroxy-4-(phenyl-(2',4',5'-trimethoxyphenyl)methyl)-xanthone (1), (+/-)-1,3,6-trihydroxy-4-(phenyl-(2',4',5'-trimethoxyphenyl)methyl)-xanthone (2), and (+/-)-1,3-dihydroxy-4-(phenyl(2',4',5'-trimethoxyphenyl)methyl)-xanthone (3) showed significant activities against S. aureus, with MIC values of 10.0, 10.0, and 25.0 mu M, respectively. Analogs (+/-)-1 and (+/-)-2 also exhibited antibacterial activities against B. subtilis, with MIC values of 50.0 and 12.5 mu M, respectively. Furthermore, (+)-3 enhanced the antibacterial activity against S. aureus, with a MIC value of 10 mu M. (C) 2017 Elsevier Ltd. All rights reserved.
• Sex difference in autism spectrum disorder (ASD)-like behaviors caused by allopregnanolone (ALLO) biosynthesis inhibition and distribution of ALLO in the brain

  Ken Ebihara, Hironori Fujiwara, Dya Fita Dibwe, Suresh Awale, Ryota Araki, Takeshi Yabe, Kinzo Matsumoto

  JOURNAL OF PHARMACOLOGICAL SCIENCES 133 3 S224 - S224 2017年03月
• Constituents of the rhizomes of Boesenbergia pandurata and their antiausterity activities against the PANC-1 human pancreatic cancer line

  Nguyen, N, Nguyen, M, Nguyen, H, Dang, P, Dibwe, D. F, Esumi, H, Awale, S

  J. Nat. Prod., 2017, 80, 141-148 80 1 141 - 148 2017年01月 [査読有り][通常論文]
   

  Human pancreatic cancer cell lines have a remarkable tolerance to nutrition starvation, which enables them to survive under a tumor microenvironment. The search for agents that preferentially inhibit the survival of cancer tells under low nutrient conditions represents a novel antiausterity strategy in anticancer drug discovery. In this investigation, a methanol extract of the rhizomes of Boesenbergia pandurata showed potent preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrient-deprived conditions, with a PC50 value of 6.6 mu g/mL. Phytochemical investigation of this, extract led to the isolation of 15 compounds, including eight new cyclohexene chalcones (1-8). The structures of the new compounds were elucidated by NMR spectroscopic data analysis. Among the isolated compounds obtained, isopanduratin A1 (14) and nicolaioidesin C (15) exhibited potent preferential cytotoxicity against PANC-1 human pancreatic canter cells under nutrition deprived conditions, with PC50 values of 1.0 and 0.84 mu M, respectively.
• Highly oxygenated antiausterity agents from the leaves of Uvaria dac

  Suresh Awale, Ahmed M. Tawila, Dya Fita Dibwe, Jun-ya Ueda, Sijia Sun, Sirivan Athikomkulchai, Chandrashaker Balachandran, Ikuo Saiki, Kinzo Matsumoto, Hiroyasu Esumi

  Bioorganic and Medicinal Chemistry Letters 27 9 1967 - 1971 2017年 [査読有り][通常論文]
   

  From the chloroform extract of the leaves of Uvaria dac, four new highly-oxygenated cyclohexene derivatives named uvaridacols I–L (1–4) were isolated together with nine previously reported compounds (5–13). Their structures were determined based on the extensive NMR spectroscopic data and circular dichroism spectroscopic analysis. Among the new compounds, uvaridacol L (4) displayed strong preferential cytotoxicity in the nutrient deprived medium against five different tested pancreatic cancer cell lines, PANC-1 (PC50, 20.1�μM), PSN-1 (PC50, 9.7�μM), MIA PaCa-2 (PC50, 29.1�μM), Capan-1 (73.0�μM) and KLM-1 (25.9�μM).
• Evaluation of synthetic coumarins for antiausterity cytotoxicity against pancreatic cancers

  Farley, C. M, Dibwe, D. F, Ueda J, Hall E.A, Awale S, Magolan J

  Bioorg. Med. Chem Lett, 2016, 26, 1471−1474. 26 5 1471 - 1474 2016年03月 [査読有り][通常論文]
   

  A series of functionalized coumarins were synthesized and evaluated for their capacity to inhibit the resistance to starvation of pancreatic cancer cells. This form of cytotoxicity, termed 'antiausterity' activity, was evaluated using a preferential cytotoxicity assay that compared cell survival in nutrient poor and nutrient rich conditions. Six of the seventeen compounds showed weak antiausterity activity against PANC-1. Compound 34 was active against PANC-1, MIA PaCa-2, and Capan-1 cancer cell lines. All of the compounds tested were simplified structural analogs of previously reported natural product leads. Six of the compounds, including 34, contain functionalized triazoles as novel potential bioisosteres of the side chain of the natural product angelmarin. Overall, the analogs were found to have low antiausterity activity relative to the corresponding natural products. (C) 2016 Elsevier Ltd. All rights reserved.
• Cassane diterpenes from the seed kernels of Caesalpinia sappan

  Hai Xuan Nguyen, Nhan Trung Nguyen, Phu Hoang Dang, Phuoc Thi Ho, Mai Thanh Thi Nguyen, Mao Van Can, Dya Fita Dibwe, Jun-ya Ueda, Suresh Awale

  PHYTOCHEMISTRY 122 286 - 293 2016年02月 

  Eight structurally diverse cassane diterpenes named tomocins A-H were isolated from the seed kernels of Vietnamese Caesalpinia sappan Linn. Their structures were determined by extensive NMR and CD spectroscopic analysis. Among the isolated compounds, tomocin A, phanginin A, F, and H exhibited mild preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrition-deprived condition without causing toxicity in normal nutrient-rich conditions. (C) 2016 Elsevier Ltd. All rights reserved.
• A new cassane-type diterpene from the seed of caesalpinia sappan

  Hai Xuan Nguyen, Nhan Trung Nguyen, Phu Hoang Dang, Phuoc Ho Thi, Mai Thanh Thi Nguyen, Mao Van Can, Dya Fita Dibwe, Jun-Ya Ueda, Kinzo Matsumoto, Suresh Awale

  Natural Product Communications 11 6 723 - 724 2016年 [査読有り][通常論文]
   

  Phytochemical investigation of the CH2Cl2 extract of the Vietnamese medicinal plant Caesalpinia sappan Linn resulted in the isolation of a new cassane-type diterpene named tomocin I (1). Its chemical structure was determined by NMR spectroscopic and mass spectrometric analysis.
• Anti-austeritic constituents of Congolese medicinal plant Aframomum melegueta

  Dibwe, D. F, Awale, S, Morita, H, Tezuka, Y

  Nat. Prod. Commun, 2015, 10, 997−999 10 6 997 - 999 2015年06月 [査読有り][通常論文]
   

  In the course of our search for anticancer agents based on a novel anti-austerity strategy, we found that the CHCl3 extract of the roots of Aflamomum melegueta (Zingiberaceae), collected in the Democratic Republic of Congo, killed PANC-1 human pancreatic cancer cells preferentially in nutrient-deprived medium (NDM). Phytochemical investigation of the CHCl3 extract led to the isolation of seven known compounds [(-)-buplerol (1), (-)-arctigenin (2), (E)-14-hydroxy-15-norlabda-8(17),12-dien-16-al (3), labda-8(17),12-dien-15,16-dial (4), 16-oxo-8(17),12(E)-labdadien-15-oic acid (5), 5-hydroxy-7-methoxyflavone (6), and apigenin (7)]. In addition to the previously reported preferentially cytotoxic compound, (-)-arctigenin (2, PC50 0.5 mu M), (-)-buplerol (1) also displayed potent preferential cytotoxicity with a PC50 value of 8.42 mu M and triggered apoptosis-like PANC-1 cell death in NDM.
• Muchimangins E and F: novel diphenylmethyl-substituted xanthones from Securidaca longepedunculata.

  Dibwe, D. F, Awale, S, Kadota, S, Morita, H, Tezuka, Y

  Tetrahedron Lett, , 2014, 55, 1916-1919. 55 11 1916 - 1919 2014年03月 [査読有り][通常論文]
   

  Two new highly oxygenated xanthones, named muchimangins E (1) and F (2), have been isolated from the root of Securidaca longepedunculata (Polygalaceae). Their structures were elucidated by the analyses of spectral data to be a novel xanthone with a diphenylmethyl substituent at C-2. Moreover, the structures of muchimangins B (4) and C (5) were revised by careful analysis of the spectral data and by comparing their NMR data with those of 1 and 2, to be xanthones with the diphenylmethyl substituent at C-2, not at C-4 reported previously. (c) 2014 Elsevier Ltd. All rights reserved.
• New guaian-type sesquiterpene from Wikstroemia indica

  Mamoru Kato, Yu-Min He, Dya Fta Dibwe, Feng Li, Suresh Awale, Shigetoshi Kadota, Yasuhiro Tezuka

  Natural Product Communications 9 1 1 - 2 2014年 [査読有り][通常論文]
   

  From a MeOH extract of powdered roots of Wikstroemia indica, we isolated a new guaian-type sesquiterpene (1) and two known guaian-type sesquiterpenes [oleodaphnal (2), 1α,7α,10αH-guaia-4,11-dien-3-one (3 )], together with twelve known compounds: (+)-arctigenin, (+)-matairesinol, (+)-trachelogenin, (+)-nortrachelogenin, (+)-hinokinin, (+)-kusunokinin, 7-methoxycoumarin, 7-hydroxycoumarin (umbelliferone), daphnogitin, daphnoretin, salicifoliol, and (-)-pinoresinol. The structure of compound 1 was determined to be 4,10,11-guaiatrien-3-one-14-oic acid, by the analyses of spectral data.
• Antiausterity activity of arctigenin enantiomers: Importance of (2R,3R)-absolute configuration

  Suresh Awale, Mamoru Kato, Dya Fita Dibwe, Feng Li, Chika Miyoshi, Hiroyasu Esumi, Shigetoshi Kadota, Yasuhiro Tezuka

  Natural Product Communications 9 1 79 - 82 2014年 [査読有り][通常論文]
   

  From a MeOH extract of powdered roots of Wikstroemia indica, six dibenzyl-γ-butyrolactone-type lignans with (2S,3S)-absolute configuration [(+)-arctigenin (1), (+)-matairesinol (2), (+)-trachelogenin (3), (+)-nortrachelogenin (4), (+)-hinokinin (5), and (+)-kusunokinin (6)] were isolated, whereas three dibenzyl-γ-butyrolactone-type lignans with (2R,3R)-absolute configuration [(-)-arctigenin (1*), (-)-matairesinol (2*), (-)-trachelogenin (3*)] were isolated from Trachelospermum asiaticum. The in vitro preferential cytotoxic activity of the nine compounds was evaluated against human pancreatic PANC-1 cancer cells in nutrient-deprived medium (NDM), but none of the six lignans (1-6) with (2S,3S)-absolute configuration showed preferential cytotoxicity. On the other hand, three lignans (1*-3*) with (2R,3R)-absolute configuration exhibited preferential cytotoxicity in a concentration-dependent manner with PC50 values of 0.54, 6.82, and 5.85 μM, respectively. Furthermore, the effect of (-)- and (+)-arctigenin was evaluated against the activation of Akt, which is a key process in the tolerance to nutrition starvation. Interestingly, only (-)-arctigenin (1*) strongly suppressed the activation of Akt. These results indicate that the (2R,3R)-absolute configuration of (-)-enantiomers should be required for the preferential cytotoxicity through the inhibition of Akt activation.
• Two New Diphenylmethyl-substituted Xanthones from Securidaca longepedunculata

  Dya Fita Dibwe, Suresh Awale, Shigetoshi Kadota, Hiroyuki Morita, Yasuhiro Tezuka

  Natural Product Communications 9 5 655 - 657 2014年 [査読有り][通常論文]
   

  Two new diphenylmethyl-substituted xanthones, named muchimangins K (1) and L (2), have been isolated from the roots of Securidaca longepedunculata (Polygalaceae) collected in the Democratic Republic of Congo. Their structures were established by analyses of the spectral data, including 2D NMR spectra, to be 1,3,6,8-tetrahydroxy-2,5-dimethoxy-4-[1-(2,4,5-trimethoxyphenyl)-1- phenylmethyl]xanthone (1) and 1,3,6-trihydroxy-4,7-dimethoxy-2-[1-(2,4,5- trimethoxyphenyl)-1-phenylmethyl]xanthone (2).
• A new polyoxygenated cyclohexane and other constituents from Kaempferia rotunda and their cytotoxic activity

  Subehan, Lee S, Dibwe D. F, Tezuka Y, Morita H

  Natural Product Research 28 20 1754 - 1759 2014年 [査読有り][通常論文]
   

  The isolation of secondary metabolites from a methanolic extract of Kaempferia rotunda yielded 12 compounds (1-12), including a new polyoxygenated cyclohexane compound, (-)-3-acetyl-4-benzoyl-1-benzoyloxymethyl-1,6-diepoxycyclohexan-2,3,4,5-tetrol (1). The structures of the isolated compounds were determined based on their spectroscopic data and comparison with references. All of the isolated compounds were tested for their cytotoxic activity against pancreatic (PSN-1) and breast (MDA-MB231) cancer cell lines. Compound 12 showed moderate cytotoxic activity against PSN-1 and MDA-MB231 without showing any cytotoxicity against the normal cell line, TIG-3.
• Heptaoxygenated xanthones as anti-austerity agents from Securidaca longepedunculata.

  Dibwe D. F, Awale, S, Kadota, S, Morita H, Tezuka, Y

  Bioorg. Med. Chem, 2013, 21, 7663-7668. 21 24 7663 - 7668 2013年12月 [査読有り][通常論文]
   

  In a course of our search for anticancer agent based on a novel anti-austerity strategy, we found that the CHCl3 extract of the roots of Securidaca longepedunculata (Polygalaceae), collected at Democratic Republic of Congo, killed PANC-1 human pancreatic cancer cells preferentially in nutrient-deprived medium (NDM). Phytochemical investigation on the CHCl3 extract led to the isolation of 28 compounds including five new polymethoxylated xanthones [1,6,8-trihydroxy-2,3,4,5-tetramethoxyxanthone (1), 1,6-dihydroxy-2,3,4,5,8-pentamethoxyxanthone (2), 8-hydroxy-1,4,5,6-tetramethoxy-2,3-methylenedioxyxanthone (3), 4,6,8-trihydroxy-1,2,3,5-tetramethoxyxanthone (4), 4,8-dihydroxy-1,2,3,5,6-pentamethoxyxanthone (5)] and a new benzyl benzoate [benzyl 3-hydroxy-2-methoxybenzoate (6)]. Among them, 1,6,8-trihydroxy-2,3,4,5-tetramethoxyxanthone (1) and 1,6-dihydroxy-2,3,4,5,8-pentamethoxyxanthone (2) displayed the potent preferential cytotoxicity with PC50 of 22.8 and 17.4 mu M, respectively. They triggered apoptosis-like PANC-1 cell death in NDM with a glucose-sensitive mode. (C) 2013 Elsevier Ltd. All rights reserved.
• Synthesis and antitumor evaluation of arctigenin derivatives based on antiausterity strategy

  Kudou N, Taniguchi A, Sugimoto K, Matsuya Y, Kawasaki M, Toyooka N, Miyoshi C, Awale S, Dibwe D. F, Esumi H, Kadota S, Tezuka Y

  Eur. J. Med. Chem., 2013, 60, 76-88. 60 76 - 88 2013年02月 [査読有り][通常論文]
   

  A series of new (-)-arctigenin derivatives with variably modified O-alkyl groups were synthesized and their preferential cytotoxicity was evaluated against human pancreatic cancer cell line PANC-1 under nutrient-deprived conditions. The results showed that monoethoxy derivative 4i (PC50, 0.49 mu M), diethoxy derivative 4h (PC50, 0.66 mu M), and triethoxy derivative 4m (PC50, 0.78. mu M) showed the preferential cytotoxicities under nutrient-deprived conditions, which were identical to or more potent than (-)-arctigenin (1) (PC50, 0.80 mu M). Among them, we selected the triethoxy derivative 4m and examined its in vivo antitumor activity using a mouse xenograft model. Triethoxy derivative 4m exhibited also in vivo antitumor activity with the potency identical to or slightly more than (-)-arctigenin (1). These results would suggest that a modification of (-)-arctigenin structure could lead to a new drug based on the antiausterity strategy. (C) 2012 Elsevier Masson SAS. All rights reserved.
• Damnacanthal from the Congolese medicinal plant Garcinia huillensis has a potent preferential cytotoxicity against human pancreatic cancer PANC-1 cells.

  Dibwe D. F, Awale, S, Kadota, S, Tezuka, Y

  Phytother. Res, 2012, 26, 1920-1926. 26 12 1920 - 1926 2012年12月 [査読有り][通常論文]
   

  Screening of eight Congolese medicinal plants showed that the CHCl3 and MeOH extracts of Aframomum melegueta (PC50 = 47.8 mu g/mL and 13.8 mu g/mL, respectively) and CHCl3 extracts of Garcinia huillensis (PC50 = 17.8 mu g/mL) and Securidaca longepedunculata (PC50 = 23.4 mu g/mL) had preferential cytotoxicity against human pancreatic cancer PANC-1 cells under nutrient-deprived conditions. The active constituents of the CHCl3 extract of G. huillensis were examined and 12 known anthraquinones were identified. Among them, damnacanthal (1) caused preferential necrotic cell death of PANC-1 and PSN-1 cells under nutrient-deprived and serum-sensitive conditions (PC50 = 4.46 mu m and 3.77 mu m, respectively). Copyright (c) 2012 John Wiley & Sons, Ltd.
• Muchimangins A–D: novel diphenylmethyl-substituted xanthones from Securidaca longepedunculata.

  Dibwe D. F, Awale, S, Kadota, S, Tezuka, Y

  Tetrahedron Lett, 2012, 53, 6186-6190. 53 46 6186 - 6190 2012年11月 [査読有り][通常論文]
   

  Four new highly oxygenated xanthones, named muchimangins A-D (1-4), with a diphenylmethyl substituent have been isolated as extremely minor constituents from the root of Securidaca longepedunculata (Polygalaceae). Among them, muchimangin B(2) induced an apoptotic-like cell death of human pancreatic cancer PANC-1 cell line preferentially in nutrient deprived condition with PC50 of 38.9 mu M. (C) 2012 Elsevier Ltd. All rights reserved.
• Anti-austerity agents from Rhizoma et Radix Notopterygii (Qianghuo)

  Feng Li, Yukari Okamura, Dyafita Dibwe, Suresh Awale, Shigetoshi Kadota, Yasuhiro Tezuka

  Planta Medica 78 8 796 - 799 2012年 [査読有り][通常論文]
   

  During a search for potent anticancer agents from natural products based on an anti-austerity strategy, we found that a CHClextract of Rhizoma et Radix Notopterygii (Qianghuo), a Chinese crude drug, exhibited strong cytotoxicity against PANC-1 human pancreatic cancer cells, with a PCvalue of 17.5 g/mL. Further fractionation and purification of this bioactive extract led to the isolation of 19 known compounds (1-19). The in vitro preferential cytotoxicity of the isolates was evaluated against two human pancreatic cancer cell lines, PANC-1 and PSN-1. Among the compounds isolated, ostruthin (7) displayed the most potent activity against both PANC-1 (PC 7.2 M) and PSN-1 (PC 7.8 M) cells in nutrient-deprived medium (NDM) and may have induced necrotic nutrient-deprived PANC-1 cell death. © Georg Thieme Verlag KG Stuttgart · New York.
• Uvaridacols E-H, highly oxygenated antiausterity agents from Uvaria dac

  Suresh Awale, Jun-Ya Ueda, Sirivan Athikomkulchai, Dya Fita Dibwe, Sherif Abdelhamed, Satoru Yokoyama, Ikuo Saiki, Ryuta Miyatake

  Journal of Natural Products 75 11 1999 - 2002 2012年 [査読有り][通常論文]
   

  Chemical investigation of the stems of Uvaria dac yielded four new highly oxygenated cyclohexene derivatives named uvaridacols E-H (1-4). Their structures were established through NMR and circular dichroism spectroscopic analysis. Uvaridacols E (1), F (2), and H (4) displayed weak preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrition-deprived conditions in a concentration-dependent manner, without causing toxicity in normal nutrient-rich conditions. © 2012 The American Chemical Society and American Society of Pharmacognosy.
• Muchimangins G-J: fully-substituted xanthones with a diphenylmethyl substitutent from Securidaca longepedunculata

  Dibwe, D. F, Awale, S, Kadota, S, Morita, H, Tezuka, Y

  J. Nat. Prod., 2014, 77 (5), 1241–1244. [査読有り][通常論文]
  
• Tshilanda, D. D, Onyamboko, D. N, Babady-B, P, Ngbolua, K. N; Tshibangu, D. S, Dibwe, D. F., Mpiana, P. T.

  Anti-sickling activity, ursolic acid, isolated, from the, leaves of Ocimum, gratissimum L. (Lamiaceae

  Nat. Prod. Bioprospect. 2015, 5 (4), 215-221. [査読有り][通常論文]
  
• Preferential cytotoxicity of crude drugs used in Kampo medicines against human pancreatic cancer PANC-1 and PSN-1 cells

  Lee, S, Dibwe, D. F, Feng, Li, Morita, H, Tezuka, Y

  Traditional & kampo medicine, 2015, 2 (2), 35-−42. [査読有り][通常論文]
  
• Syntheses of benzophenone- xanthone hybrid polyketides and their antibacterial activities

  Kodama, T, Ito, T, Dibwe, D.F, Woo, S-Y, Morita, H

  Bioorg. Med. Chem Lett 26 1471 - 1474 [査読有り][通常論文]
  

講演・口頭発表等

• Discovery of potential antiausterity agents from Thai Piper ribesoides  [通常講演]

  Dibwe D.F

  The 139th Annual Meeting of the Pharmaceutical Society of Japan. 2019年03月
• Discovery of anti-austerity agents from Derris scandens  [通常講演]

  Dibwe D. F

  The 65th Annual Meeting of the Japanese Society of Pharmacognosy 2018年09月
• Prenylated isoflavones from Thai Derris scandens and their anti-austerity activity  [通常講演]

  Dibwe D.F

  The 5th Toyama-Basel Joint Symposium on Pharmaceutical Research and Drug Development 2018年08月
• Discovery of potential anti austerity agents from Thai Derris scandens  [通常講演]

  Dibwe D.F

  The 138th Annual Meeting of the Pharmaceutical Society of Japan , Kanazawa 2018年03月
• Chemical Constituents of Piper longum and their Antiausterity activity  [通常講演]

  Dibwe D.F

  Toyama Science Gala 2017 2017年09月

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