Screening for small molecule inhibitors of BMP-Induced osteoblastic differentiation from Indonesian marine invertebrates
Yamazak H, Ohte S, Rotinsulu H, Wewengkang DS, Sumilat DA, Abdjul DB, Maarisit W, Kapojos MM, Namikoshi M, Katagiri T, Tomoda H, Uchida R
Marine drugs . 2020, 18
Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disorder with heterotopic ossification (HO) in soft tissues. The abnormal activation of bone morphogenetic protein (BMP) signaling by a mutant activin receptor-like kinase-2 (ALK2) leads to the development of HO in FOP patients, and, thus, BMP signaling inhibitors are promising therapeutic applications for FOP. In the present study, we screened extracts of 188 Indonesian marine invertebrates for small molecular inhibitors of BMP-induced alkaline phosphatase (ALP) activity, a marker of osteoblastic differentiation in a C2C12 cell line stably expressing ALK2(R206H) (C2C12(R206H) cells), and identified five marine sponges with potent ALP inhibitory activities. The activity-guided purification of an EtOH extract of marine sponge Dysidea sp. (No. 256) resulted in the isolation of dysidenin (1), herbasterol (2), and stellettasterol (3) as active components. Compounds 1–3 inhibited ALP activity in C2C12(R206H) cells with IC50 values of 2.3, 4.3, and 4.2 µM, respectively, without any cytotoxicity, even at 18.4–21.4 µM. The direct effects of BMP signaling examined using the Id1WT4F-luciferase reporter assay showed that compounds 1–3 did not decrease the reporter activity, suggesting that they inhibit the downstream of the Smad transcriptional step in BMP signaling.
Evaluation of anti-mycobacterial compounds in a silkworm infection model with Mycobacteroides abscessus
Hosoda K, Koyama N, Hamamoto H, Yagi A, Uchida R, Kanamoto A, TomodaH
Molecules, 2020, 25; E4971
Among four mycobacteria, Mycobacterium avium, M. intracellulare, M. bovis BCG and Mycobacteroides (My.) abscessus, we established a silkworm infection assay with My. abscessus. When silkworms (fifth-instar larvae, n=5) were infected through the hemolymph with My. abscessus (7.5 × 10^7 CFU/larva) and bred at 37 °C, they all died around 40 h after injection. Under the conditions, clarithromycin and amikacin, clinically used antimicrobial agents, exhibited therapeutic effects in a dose-dependent manner. Furthermore, five kinds of microbial compounds, lariatin A, nosiheptide, ohmyungsamycins A and B, quinomycin and steffimycin, screened in an in vitro assay to observe anti-My. abscessus activity from 400 microbial products were evaluated in this silkworm infection assay. Lariatin A and nosiheptide exhibited therapeutic efficacy. The silkworm infection model with My. abscessus is useful to screen for therapeutically effective anti-My. abscessus antibiotics
Voluhemins, New Inhibitors of Sterol O-acyltransferase, Produced by Volutella Citrinella BF-0440
Ohshiro T, Morita H, Elyza Aiman Azizah Nur, Hosoda K, Uchida R, Tomoda H
J Antibiot. 2020, 73; 748-755
New compounds, designated voluhemins A (1) and B (2), are isolated from the culture broth of the fungal strain Volutella citrinella BF-0440 along with structurally related known NK12838 (3). Spectroscopic data, including 1D and 2D NMR, elucidated their structures. Compounds 1–3 have a common indoline-diterpene core and two additional isoprenyl moieties. Compounds 1 and 3 contain a hemiaminal unit, while 2 is O-methylated 1. Their inhibitory activities toward sterol O-acyltransferase (SOAT) 1 and 2 isozymes in SOAT1- and SOAT2-expressing Chinese hamster ovary (CHO) cells show that 2 selectively inhibits the SOAT2 isozyme.
Screening of Indonesian edible plants for bioactive constituents and a new protein tyrosine phosphatase 1B inhibitory acylbenzene derivative from leaves of Indonesian Syzygium polyanthum
Kapojos MM, Abdjul DB, Yamazaki H, Yagi A, Uchida R
Chem. Pharm. Bull. 2020 68; 903-906
Bioassay screening using Indonesian plants, such as traditional foods (vegetables, spices, and tea) and folk medicinal herbs, identified eight protein tyrosine phosphatase (PTP) 1B inhibitory and two antibacterial plants. The leaves of Syzygium polyanthum (Wight) Walp. were examined in more detail to define PTP1B inhibitory components, resulting in the isolation of a new active acylbenzene (1) along with four related congeners of 1 (2–5) and four oleanane triterpenes (6–9). The structure of 1 was elucidated as 12-oxo-12-(2,3,5-trihydroxy-4-methylphenyl)dodecanoic acid based on its spectroscopic data. The acylbenzenes 1 and 3–5 inhibited PTP1B activity with IC50 values ranging between 9.5 and 14 µM, whereas the triterpenes 7–9 also suppressed this activity with IC50 values of 3.3–5.7 µM.
Antifungal trichothecene sesquiterpenes obtained from the culture broth of marine-derived Trichoderma cf. brevicompactum and their structure-activity relationship
Yamazaki H, Yagi A, Takahashi O, Yamaguchi Y, Saito A, Namikoshi M, Uchida R
Bioorg. Med. Chem. Lett. 2020, 30; 127375 (2020)
Two new trichothecene sesquiterpenes, trichobreols D (1) and E (2), were isolated from the culture broth of marine-derived Trichoderma cf. brevicompactum together with trichobreol A (3). The structures of 1 and 2 were assigned on the basis of their spectroscopic data. Compound 1 inhibited the growth of two yeast-like fungi, Candida albicans and Cryptococcus neoformans, with equivalent MIC values (6.3 μg/mL), while 2 gave MIC values of 12.5 and 25 μg/mL, respectively. The antifungal activities of five semisynthetic derivatives (4-8) prepared from 3 were evaluated and compared to investigate the preliminary structure-activity relationship.
Epipolythiodiketopiperazine and trichothecene derivatives from the NaI-containing fermentation of marine-derived Trichoderma cf. brevicompactum
Yamazaki H, Takahashi O, Kirikoshi R, Yagi A, Ogasawara T, Bunya Y, Rotinsulu H, Uchida R, Namikoshi M.
J Antibiot. 2020, 73: 559-567.
The marine-derived fungus Trichoderma sp. TPU199 (cf. Trichoderma brevicompactum) produces pretrichodermamide A (1) and gliovirin (2), which possess a rare type of epipolythiodiketopiperazine (ETP) structure with a disulfide bridge between the α- and β-positions of two amino acid residues. We previously reported that this strain gave the halogenated ETPs, DC1149B (4), DC1149R (6), and iododithiobrevamide (7), when fermented with sodium halides (NaCl, NaBr, and NaI). Further analyses of the metabolites obtained under NaI-containing culture conditions resulted in the isolation of two new ETP derivatives (11 and 12) and three new trichothecene sesquiterpenes (13–15). The structures of 11 and 12, including their absolute configurations, were elucidated based on spectroscopic data for 11 and 12 and comparisons with those for 1 and related compounds, revealing that 11 was an epimer of 1 at the C-5 position and 12 was a trithio-derivative of 11. The structures of 13–15 were established by analyzing their 1D and 2D NMR data. The absolute configurations of 13–15 were assigned by comparing their experimental electronic circular dichroism (ECD) spectra with the calculated ECD spectrum of 13.
Production of an α-pyrone metabolite and microbial transformation of isoflavones by an Indonesian Streptomyces sp.
Wewengkang DS, Yamazaki H, Takahashi M, Togashi T, Rotinsulu H, Sumilat DA, Namikoshi M
J Asian Nat Prod Res 2020, 22; 754-761
A benzyl-α-pyrone metabolite, streptpyrone A (1), was obtained together with three known isoflavonoids, daidzein-7-O-α-l-rhamnoside (2), genistein-7-O-α-l-rhamnoside (3), and daidzein (4), from the culture broth of an Indonesian actinomycete Streptomyces sp. TPU1401A. The structure of 1, elucidated based on its spectroscopic data, has been reported as a synthetic compound. However, this is the first report of the isolation of 1 as a metabolite of microbial origin. Strain TPU1401A exhibited the ability to transform the isoflavone aglycones 4 and genistein (5) into the 7-O-glycosides 2 and 3, respectively. Compounds 2 and 3 promoted the growth of strain TPU1401A more effectively than compounds 4 and 5. These results suggest that strain TPU1401A utilizes isoflavone glycosides to promote growth by transforming isoflavones through microbial glycosidation.
Synthesis and Absolute Configuration of Habiterpenol
Konya M, Shimoyama K, Arima S, Fukuda T, Uchida R, Tomoda H, Nagamitsu T.
Org Lett. 2020, 22: 5131-5134.
The synthesis of habiterpenol, a G2 checkpoint inhibitor, was achieved through the stereoselective Ti(III)-mediated radical cyclization of a β-epoxide as the key reaction. Moreover, the absolute configuration of habiterpenol was determined.
Polyketide glycosides phialotides A to H, new potentiators of amphotericin B activity, produced by Pseudophialophora sp. BF-0158
Yagi A, Uchida R, Kobayashi K, Tomoda H
J Antibiot. 2020 73: 211-223
Eight new potentiators of antifungal amphotericin B (AmB) activity, phialotides A to H, were isolated from the fermentation broths of the rare fungus Pseudophialophora sp. BF-0158. The structures of phialotides were elucidated by spectroscopic analyses, including NMR and MS, and degradation studies. Phialotides were novel polyketide glycosides consisting of a 1,3-dimethylbut-1-ene (C6-unit) repeating substructure and one to three hexopyranoses. None of the phialotides exhibited antifungal activity, whereas all potentiated AmB activity against several fungi. Phialotide F was the most effective potentiator of AmB activity against Candida albicans, with a decrease in the MIC from 0.50 to 0.016 µg/ml being observed in combination with phialotide F at 1.0 µg/ml.
日本薬学会第 141 年会: 国立京都国際会館 (京都) 2020 年 3 月 25 日~28 日
山口 優雅、八木 瑛穂、山﨑 寛之、内田 龍児
骨分化阻害物質 scopranone とアミノ酸との反応
金田 幸歩、大手 聡、李 大葵、大多和 正樹、内田 龍児、長光 亨、供田 洋
インドネシア産食用植物に由来するprotein tyrosine phosphatase 1B阻害物質の探索
山崎 寛之、Kapojos Magie M. 、Abdjul Delfly B. 、千田 貴大、八木 瑛穂、内田 龍児
宮城県産 Petasites japonicus より得られたセスキテルペン類のprotein tyrosine phosphatase 1B 阻害活性
山﨑 寛之、柘植 勇人、千田 貴大、石井 望美、大森 かりん、高橋 泰大、八木澤 裕太、遠藤 伶、内田 龍児
Amphotericin B 活性増強作用を有する simpotentin の全合成と絶対立体配置の決定
大多和 正樹、李 大葵、清水 恵里、齊藤 惇、近藤 あり子、八木 瑛穂、内田 龍児、供田 洋、長光 亨
第62回 天然有機化合物討論会, 名古屋, 2020年9月
真菌 Volutella citrinella BF-0440 株が生産するsterol O-acyltransferase阻害剤とその構造活性相関
小林 啓介, 大城 太一, Elyza Aiman Azizah Nur, 森田 遥, 内田 龍児, 供田 洋
山﨑 寛之, Magie Melanie Kapojos, Delfly Booby Abdjul, 八木 瑛穂, 浪越通夫, 内田 龍児