通过分离新的 (-)-(5E)-(8R)-(14Z)-霉噻唑类似物，进一步探讨独特的海绵衍生生物碱的性质。
Further Probing the Properties of a Unique Sponge-derived Alkaloid Through the Isolation of a New (-)-(5E)-(8R)-(14Z)-Mycothiazole Analogue.
发表日期：2024 Sep 30
作者：
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
来源：
JOURNAL OF NATURAL PRODUCTS
摘要：
从瓦努阿图 C. mycofijiensis 标本中放大分离 ( )-(5Z)-(8S)-(14Z)-霉菌噻唑 (1)，以半合成 ( )-(5Z)-(8S)-8-O-乙酰基- (14Z)-霉菌噻唑 (2) 揭示了一种新的非对映异构体，(-)-(5E)-(8R)-(14Z)-霉菌噻唑 (4)。使用 HRMS、NMR 确定 4 的结构，并将旋光度与 (-)-(5Z)-(8R)-(14Z)-mycothiazol (3) 和 2 进行比较。2 在小鼠中的最大耐受剂量为 0.1 mg /公斤。 4 在 PANC-1 和 HepG2 癌细胞系中的 IC50 分别为 111.6 和 115.0 nM。对秀丽隐杆线虫 4 的评估显示，与 1-2 相比，耗氧量相似，并且所有化合物均显着延长了寿命。 Δ5,6 处的 Z 方向对于皮摩尔细胞毒性至关重要，但对于线粒体抑制则不然。
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.