Further Probing the Properties of a Unique Sponge-derived Alkaloid Through the Isolation of a New (-)-(5E)-(8R)-(14Z)-Mycothiazole Analogue.

IF 3.3 2区生物学 Q2 CHEMISTRY, MEDICINAL

Journal of Natural Products Pub Date : 2024-10-25 Epub Date: 2024-09-30 DOI:10.1021/acs.jnatprod.4c00691

Joe A Gerke, Sofia F Odron, Juri Kim, Naibedya Dutta, Jacqueline G Clarke, Joseph Media, David A Coppage, Maria Oorloff, Athena Alcala, Gilberto Garcia, Marissa E F Kang, Cy L Gerke, Jacob C Peterson, Joseph D Morris, Ryo Higuchi-Sanabria, Frederick A Valeriote, Phillip Crews, Tyler A Johnson

{"title":"Further Probing the Properties of a Unique Sponge-derived Alkaloid Through the Isolation of a New (-)-(5E)-(8R)-(14Z)-Mycothiazole Analogue.","authors":"Joe A Gerke, Sofia F Odron, Juri Kim, Naibedya Dutta, Jacqueline G Clarke, Joseph Media, David A Coppage, Maria Oorloff, Athena Alcala, Gilberto Garcia, Marissa E F Kang, Cy L Gerke, Jacob C Peterson, Joseph D Morris, Ryo Higuchi-Sanabria, Frederick A Valeriote, Phillip Crews, Tyler A Johnson","doi":"10.1021/acs.jnatprod.4c00691","DOIUrl":null,"url":null,"abstract":"Scale-up isolation of (+)-(5Z)-(8S)-(14Z)-mycothiazole (1) from Vanuatu specimens of C. mycofijiensis to semisynthesize (+)-(5Z)-(8S)-8-O-acetyl-(14Z)-mycothiazole (2) revealed a new diastereomer, (-)-(5E)-(8R)-(14Z)-mycothiazole (4). The structure of 4 was determined using HRMS, NMR, and comparing optical rotation to (-)-(5Z)-(8R)-(14Z)-mycothiazole (3) and 2. The maximum tolerated dose of 2 in mice was 0.1 mg/kg. The IC50 of 4 in PANC-1 and HepG2 cancer cell lines was 111.6 and 115.0 nM. Evaluation of 4 in C. elegans showed similar oxygen consumption compared to 1-2, and all compounds significantly increased the lifespan. The Z orientation at Δ5,6 is crucial for picomolar cytotoxicity but not for mitochondrial inhibition.","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":" ","pages":"2523-2529"},"PeriodicalIF":3.3000,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11534373/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Natural Products ","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1021/acs.jnatprod.4c00691","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/30 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

Scale-up isolation of (+)-(5Z)-(8S)-(14Z)-mycothiazole (1) from Vanuatu specimens of C. mycofijiensis to semisynthesize (+)-(5Z)-(8S)-8-O-acetyl-(14Z)-mycothiazole (2) revealed a new diastereomer, (-)-(5E)-(8R)-(14Z)-mycothiazole (4). The structure of 4 was determined using HRMS, NMR, and comparing optical rotation to (-)-(5Z)-(8R)-(14Z)-mycothiazole (3) and 2. The maximum tolerated dose of 2 in mice was 0.1 mg/kg. The IC₅₀ of 4 in PANC-1 and HepG2 cancer cell lines was 111.6 and 115.0 nM. Evaluation of 4 in C. elegans showed similar oxygen consumption compared to 1-2, and all compounds significantly increased the lifespan. The Z orientation at Δ^5,6 is crucial for picomolar cytotoxicity but not for mitochondrial inhibition.

查看原文本刊更多论文

通过分离一种新的(-)-(5E)-(8R)-(14Z)-霉噻唑类似物，进一步探索一种独特的海绵生物碱的特性。

从瓦努阿图的 C. mycofijiensis 标本中放大分离 (+)-(5Z)-(8S)-(14Z)-mycothiazole (1)，半合成 (+)-(5Z)-(8S)-8-O-acetyl-(14Z)-mycothiazole (2)，发现了一种新的非对映异构体，(-)-(5E)-(8R)-(14Z)-mycothiazole (4)。4 的结构是通过 HRMS、NMR 和比较 (-)-(5Z)-(8R)-(14Z)-mycothiazole (3) 和 2 的光学旋转来确定的。小鼠对 2 的最大耐受剂量为 0.1 毫克/千克。4 在 PANC-1 和 HepG2 癌细胞系中的 IC50 分别为 111.6 和 115.0 nM。在秀丽隐杆线虫体内对 4 的评估显示，其耗氧量与 1-2 相似，而且所有化合物都能显著延长秀丽隐杆线虫的寿命。Δ5,6处的Z取向对于皮摩尔细胞毒性至关重要，但对于线粒体抑制作用却不重要。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Journal of Natural Products 生物-药学

CiteScore

9.10

自引率

5.90%

发文量

294

审稿时长

2.3 months

期刊介绍： The Journal of Natural Products invites and publishes papers that make substantial and scholarly contributions to the area of natural products research. Contributions may relate to the chemistry and/or biochemistry of naturally occurring compounds or the biology of living systems from which they are obtained. Specifically, there may be articles that describe secondary metabolites of microorganisms, including antibiotics and mycotoxins; physiologically active compounds from terrestrial and marine plants and animals; biochemical studies, including biosynthesis and microbiological transformations; fermentation and plant tissue culture; the isolation, structure elucidation, and chemical synthesis of novel compounds from nature; and the pharmacology of compounds of natural origin. When new compounds are reported, manuscripts describing their biological activity are much preferred. Specifically, there may be articles that describe secondary metabolites of microorganisms, including antibiotics and mycotoxins; physiologically active compounds from terrestrial and marine plants and animals; biochemical studies, including biosynthesis and microbiological transformations; fermentation and plant tissue culture; the isolation, structure elucidation, and chemical synthesis of novel compounds from nature; and the pharmacology of compounds of natural origin.