2019
 
Inhibition of interleukin-8 production in interleukin-1 stimulated human monocytic THP-1 cells by N,N-didesmethylgrossularine-1 obtained from an ascidian Polycarpa aurata collected in North Sulawesi.
Sumilat DA, Oda T, Wewengkang DS, Namikoshi M, Yamazaki H.
IOP Conf Ser: Mater Sci Eng. 2019. 567: 012021. 
doi: 10.1088/1757-899X/567/1/012021
 
Abstract
N,N-Didesmethylgrossularine-1 (DDMG-1) has a rare β-carboline structure and was isolated from an Indonesian ascidian Polycarpa aurata as an active component against tumor necrosis factor (TNF)α production in lipopolysaccharine (LPS)-stimulated murine macrophase-like RAW 264.7 cells as reported in our previous paper. Further investigation on the inhibitory activity of DDMG-1 against the production of inflammatory cytokines in human monocytic THP-1 cells, we found that DDMG-1 reduced the excess production of IL-8 in LPS- stimulated THP-1 cells through inhibition of the mRNA level of IL-8 1κB-α degradation, and binding of NF-xfi to the target DNA site. The THP-1 cells used in this study showed the high production of IL-8 by the stimulation with TNF-α, IL-1β, and 12-O-tetradecanoylphorbol-13-acetate (PMA) as similar to LPS. DDMG-1 inhibited the IL-8 production in IL-1β-stimulated THP-1 cells but did not show an inhibitory activity in the cells stimulated by TNF-α and PMA. Therefore, DDMG-1 was specific to the IL-1β signalling pathway. These results suggested that DDMG-1 could be a useful drug candidate lead compound to control the excess production of IL-8.

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An unusual extender unit is incorporated into the modular polyketide synthase of scopranones biosynthesis.
Demachi A, Uchida R, Arima S, Nagamitsu T, Hashimoto J, Komatsu M, Kozone I, Shin-Ya K, Tomoda H, Ikeda H.
Biochemistry. 2019 58: 5066-5073. 
doi: 10.1021/acs.biochem.9b00908.
 
Abstract
Scopranones, produced by Streptomyces sp. BYK-11038, are the novel bone morphogenetic protein inhibitors characterized by atypical two scoop-like moieties and a 3-furanone moiety. Two scoop-like moieties connected to a 3-furanone have not previously been reported in natural products, and their biosynthesis must occur via a unique pathway. Feeding experiments using 13C-labeled precursors indicated that scopranones were synthesized from three acetates and three butyrates in polyketide-type biosynthesis. Genome mining of Streptomyces sp. BYK-11038 revealed that the candidate biosynthetic gene cluster contains 21 open reading frames (ORFs), including three modular polyketide synthases (PKSs; SprA, SprB, and SprC), which were composed of 4 modules with one loading module and 18 additional ORFs (SprD to SprU) spanning a distance of 55 kbp. The characterization of in-frame deletion mutants and feeding experiments with the predicted extender units indicated that two genes, sprP and sprR, encoding discrete 3-oxoacyl-ACP synthases, and a gene, sprO, encoding crotonyl-CoA reductase, were involved in assembling an unusual C8 branched extender unit, 2-(2-ethylbutyl)malonyl-CoA. Additionally, three ORFs, sprM, sprN, and sprT, encoding cytochrome P450s and a monooxygenase, are important tailoring enzymes in post-PKS modification. SprT is an essential enzyme for decarboxylative ring contraction via oxidation, which converts the 2-pyranone to a 3-furanone.

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Nectriatide, a potentiator of amphotericin B activity from Nectriaceaesp. BF-0114
Fukuda T, Nagai K, Yagi A, Kobayashi K, Uchida R, Yasuhara T, Tomoda H
J Nat Prod. 2019 82: 2673-2681.
doi:10.1021/acs.jnatprod.8b01056
 
Abstract
A new compound, designated nectriatide (1), was isolated as a potentiator of amphotericin B (AmB) activity against Candida albicans from the culture broth of Nectriaceae sp. BF-0114. This structure was elucidated based on spectroscopic analyses (1D and 2D NMR data), chemical methods, and total synthesis. Compound 1 was a unique cyclotetrapeptide consisting of l-N-methyltyrosine, anthranilic acid, l-alanine, and l-valine. Compound 1 and several synthetic derivatives, including linear peptides, potentiated AmB activity against C. albicans by up to 16-fold (the MIC value of AmB decreased from 0.5 μg/mL to 0.031 μg/mL in combination with test compound).

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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. 2019 16: 1-8.
doi.org/10.1080/10286020.2019.1635588 
 
Abstract
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.

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Total synthesis and absolute configuration of simpotentin, a potentiator of amphotericin B activity
Ohtawa M, Shimizu E, Saito A, Sakamoto S, Waki A, Kondo A, Yagi A, Uchida R, Tomoda H, Nagamitsu T.
Org Lett. 2019. 21: 5596-5599.
doi.org/10.1021/acs.orglett.9b01945 
 
Abstract
The total synthesis of simpotentin (1), a new potentiator of amphotericin B activity against Candida albicans, was achieved. Our research results enabled the access of all stereoisomers of 1 and the elucidation of the unknown absolute configuration of 1. Furthermore, one of the stereoisomers is a better amphotericin B potentiator than 1 and is an excellent lead compound for the development of a novel amphotericin B potentiator.

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Inhibition of neutral lipid synthesis by avarols from a marine sponge
OhshiroT, Kobayashi K, Suzuki A, Yamazaki H, Uchida R, Namikoshi M, Tomoda H.
Bioorg Med Chem Lett. 2019 29: 2283-2285.
doi: 10.1016/j.bmcl.2019.06.026
 
Abstract 
The effects of 14 sesquiterpene hydroquinones, including 8 marine sponge-derived avarols (1-8) and 6 semisynthetic derivatives (9-14), on lipid droplet accumulation and neutral lipid synthesis in Chinese hamster ovary (CHO) K1 cells were investigated. In intact CHO-K1 cell assays, avarol (1) markedly decreased the number and size of lipid droplets in CHO-K1 cells and exhibited the most potent inhibitory activity on the synthesis of cholesteryl ester (CE) and triglyceride (TG) with IC50 values of 5.74 and 6.80 µM, respectively. In enzyme assays, sterol O-acyltransferase (SOAT), the final enzyme involved in CE biosynthesis, and diacylglycerol acyltransferase (DGAT), the final enzyme involved in TG biosynthesis, were inhibited by 1 with IC50 values of 7.31 and 20.0 µM, respectively, which correlated well with those obtained in the intact cell assay. These results strongly suggest that 1 inhibited SOAT and DGAT activities in CHO-K1 cells, leading to a reduction in the accumulation of CE and TG in lipid droplets.

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Search for protein tyrosine phosphatase 1B inhibitors from marine organisms and induced production of new fungal metabolites by modulating culture methods.
Yamazaki H.
Yakugaku Zasshi 2019 139: 663-672. 
doi: 10.1248/yakushi.18-00221
 
Abstract 
Marine environments offer a rich source of natural products with potential therapeutic applications because the ocean covers 70% of the earth’s surface and approximately 80% of all living organisms live in the sea. Therefore we have investigated bioactive compounds from marine organisms such as marine sponges, ascidians, and marine-derived microorganisms. This review consists of two topics based on marine natural product chemistry. (1) Protein tyrosine phosphatase (PTP) 1B plays a key role as a negative regulator in the insulin and leptin signaling pathways. Accordingly, the development of PTP1B inhibitors is expected to provide new drugs for type 2 diabetes and obesity. We have been searching for new types of PTP1B inhibitors among marine organisms and identified various PTP1B inhibitors from marine sponges and fungi. This review presents their structural diversities and unique biological properties. (2) In the course of our studies on the induced production of new fungal metabolites, the Palauan marine-derived fungus, Trichoderma cf. brevicompactum TPU199, was found to produce the unusual epipolythiodiketopiperazines, gliovirin and pretrichodermamide A. Long-term static fermentation of the strain induced production of a new dipeptide, dithioaspergillazine A, whereas fermentation of the strain with NaCl, NaBr, and NaI produced the Cl and Br derivatives of pretrichodermamide A and a new iodinated derivative, iododithiobrevamide, respectively. Moreover, DMSO-added seawater medium induced the production of diketopiperazine with the unprecedented trithio-bridge, chlorotrithiobrevamide. This fermentation study on the strain as well as the structures of the metabolites obtained are described in this review.

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Simpotentin, a new potentiator of amphotericin B activity against Candida albicans, produced by Simplicillium minatense FKI-4981.
Uchida R, Kondo A, Yagi A, Nonaka K, Masuma R, Kobayashi K, Tomoda H.
J Antibiot. 2019 72: 134-140.
doi: 10.1038/s41429-018-0128-x
 
Abstract 
Simpotentin, a new potentiator of amphotericin B activity against Candida albicans and Cryptococcus neoformans, was isolated from the culture broth of Simplicillium minatense FKI-4981 by Diaion HP-20 column chromatography, centrifugal partition chromatography, and preparative HPLC. The structure of simpotentin was elucidated by spectroscopic analyses including NMR and MS. The compound has a mannose core to which two medium-chain fatty acids are linked. Simpotentin was found to potentiate amphotericin B activity against C. albicans by the microdilution method.

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Helvamide, a new inhibitor of sterol O-acyltransferase produced by the fungus Aspergillus nidulans BF-0142.
Fukuda T, Furukawa T, Kobayashi K, Nagai K, Uchida R, Tomoda H.
J Antibiot. 2019  72: 8-14.
doi: 10.1038/s41429-018-0101-8.
 
Abstract
A new piperazine derivative designated helvamide was isolated as a pair of rotamers (1 and 2) from the culture broth of the fungus Aspergillus nidulans BF-0142 along with a known helvafuranone (3). The structures of 1 and 2 were elucidated based on spectroscopic analyses by the interpretation of one-dimensional and two-dimensional nuclear magnetic resonance data, ROESY (rotational Overhauser effect spectroscopy) correlations, and a chemical method. Helvamide existed as a rotameric mixture (1 and 2) in dimethyl sulfoxide. Helvamide inhibited sterol O-acyltransferases 1 and 2 (SOAT1 and SOAT2) in enzyme-based and cell-based assays using SOAT1-expressing and SOAT2-expressing Chinese hamster ovary (CHO) cells.

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第 58 回 日本薬学会東北支部大会: 東北大学 (仙台)  令和元年 10 月 20 日

海洋糸状菌 Trichoderma cf. brevicompactum TPU199 株が生産する新規 trichothecene 類の抗真菌活性
八木 瑛穂 、山﨑 寛之 、斉藤 杏里 、浪越 通夫 、内田 龍児

Screening for PTP1B inhibitors from Indonesian edible plants
Magie M. Kapojos, Delfly B. Abdjul, Hiroyuki Yamazaki, Akiho Yagi, Ryuji Uchida
 
フキノトウ (Petasites japonicus) から単離された PTP1B 阻害物質
山﨑 寛之、石井 望美、遠藤 伶、大森かりん、高橋 泰大、八木澤 裕太、内田 龍児

 
放線菌 TMPU-A0004 株が生産する抗真菌活性物質
山口 優雅、千葉 まれの、山﨑 寛之、内田 龍児

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日本生薬学会 第 66 回年会: 北里大学 (東京)  令和元年 9 月 22 日~23 日

インドネシアにおける海洋天然資源の調査研究および 微生物による含ハロゲン二次代謝産物の効率的生産
山﨑 寛之

山﨑寛之，大城太一，Delfly B. Abdjul, 関 怜子，大手聡，供田洋，浪越通夫，内田龍児

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第 61 回天然有機化合物討論会: 広島国際会議場 (広島)  令和元年 9 月 11 日~13 日

真菌 Pseudophialophora sp. BF-0158 株が生産する新規 amphotericin B 活性増強物質 phialotide 類に関する研究
八木 瑛穂, 供田 洋, 内田 龍児

G2 checkpoint 阻害物質 (–)–habiterpenol の全合成
紺谷 深雪, 永富 翔子, 下山 健太, 内田 龍児, 供田 洋, 長光 亨 
 
新奇なスコップ状構造を有する放線菌由来 scopranone 類の生合成
出町 歩, 内田 龍児, 長光 亨, 新家 一男, 池田 治生, 供田 洋

日本薬学会第 140 年会: 幕張メッセ (千葉)  平成 31 年 3 月 20 日~23 日