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":"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。","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":"<p><p>Scale-up isolation of (+)-(5<i>Z</i>)-(8<i>S</i>)-(14<i>Z</i>)-mycothiazole (<b>1</b>) from Vanuatu specimens of <i>C. mycofijiensis</i> to semisynthesize (+)-(5<i>Z</i>)-(8<i>S</i>)-8-<i>O</i>-acetyl-(14<i>Z</i>)-mycothiazole (<b>2</b>) revealed a new diastereomer, (-)-(5<i>E</i>)-(8<i>R</i>)-(14<i>Z</i>)-mycothiazole (<b>4</b>). The structure of <b>4</b> was determined using HRMS, NMR, and comparing optical rotation to (-)-(5<i>Z</i>)-(8<i>R</i>)-(14<i>Z</i>)-mycothiazole (<b>3</b>) and <b>2</b>. The maximum tolerated dose of <b>2</b> in mice was 0.1 mg/kg. The IC<sub>50</sub> of <b>4</b> in PANC-1 and HepG2 cancer cell lines was 111.6 and 115.0 nM. Evaluation of <b>4</b> in <i>C. elegans</i> showed similar oxygen consumption compared to <b>1</b>-<b>2</b>, and all compounds significantly increased the lifespan. The <i>Z</i> orientation at Δ<sup>5,6</sup> is crucial for picomolar cytotoxicity but not for mitochondrial inhibition.</p>","PeriodicalId":47,"journal":{"name":"Journal of Natural Products ","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Further Probing the Properties of a Unique Sponge-derived Alkaloid Through the Isolation of a New (-)-(5<i>E</i>)-(8<i>R</i>)-(14<i>Z</i>)-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\":\"<p><p>Scale-up isolation of (+)-(5<i>Z</i>)-(8<i>S</i>)-(14<i>Z</i>)-mycothiazole (<b>1</b>) from Vanuatu specimens of <i>C. mycofijiensis</i> to semisynthesize (+)-(5<i>Z</i>)-(8<i>S</i>)-8-<i>O</i>-acetyl-(14<i>Z</i>)-mycothiazole (<b>2</b>) revealed a new diastereomer, (-)-(5<i>E</i>)-(8<i>R</i>)-(14<i>Z</i>)-mycothiazole (<b>4</b>). The structure of <b>4</b> was determined using HRMS, NMR, and comparing optical rotation to (-)-(5<i>Z</i>)-(8<i>R</i>)-(14<i>Z</i>)-mycothiazole (<b>3</b>) and <b>2</b>. The maximum tolerated dose of <b>2</b> in mice was 0.1 mg/kg. The IC<sub>50</sub> of <b>4</b> in PANC-1 and HepG2 cancer cell lines was 111.6 and 115.0 nM. Evaluation of <b>4</b> in <i>C. elegans</i> showed similar oxygen consumption compared to <b>1</b>-<b>2</b>, and all compounds significantly increased the lifespan. The <i>Z</i> orientation at Δ<sup>5,6</sup> is crucial for picomolar cytotoxicity but not for mitochondrial inhibition.</p>\",\"PeriodicalId\":47,\"journal\":{\"name\":\"Journal of Natural Products \",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2024-09-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"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\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","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":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Further Probing the Properties of a Unique Sponge-derived Alkaloid Through the Isolation of a New (-)-(5E)-(8R)-(14Z)-Mycothiazole Analogue.
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.
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.
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