Aphidicolin Chemistry of the Deep-Sea-Derived Fungus Botryotinia fuckeliana MCCC 3A00494
Aphidicolin Chemistry of the Deep-Sea-Derived Fungus Botryotinia fuckeliana MCCC 3A00494
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深海真菌 Botryotinia foleliana MCCC 3A00494 的 Aphidicolin 化学
DOI：
10.1021/acs.jnatprod.9b00705
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发表时间：
2019-08-01
影响因子：
5.1
通讯作者：
Yang, Xian-Wen
中科院分区：
文献类型：
--
作者：
Niu, Siwen;Xia, Jin-Mei;Yang, Xian-Wen
Aphidicolin, a potent DNA polymerase alpha inhibitor, has been explored in clinical trials for the treatment of cancer. So far, about 300 modified aphidicolins have been discovered. However, none have shown a stronger effect. Herein, we report 71 new (aphidicolins Al-A71, 1-71) and eight known (72-79) aphidicolin congeners from Botryotinia fuckeliana MCCC 3A00494, a fungus isolated from the western Pacific Ocean (-5572 m). The structures of 1-71 were determined through extensive spectroscopic analysis, X-ray crystallography, chemical derivatization, modified Mosher's method, and the ECD exciton chirality method. Compounds 54-57 and 58-64 are novel 6/6/5/6/5 pentacyclic aphidicolins featuring tetrahydrofuran and dihydrofuran rings, respectively, while compounds 65-71 are rare noraphidicolins. Aphidicolin A8 (8) significantly induced apoptosis in T24 (IC50 = 2.5 mu M) and HL-60 (IC50 = 6.1 mu M) cancer cells by causing DNA damage. By docking its structure to the human DNA polymerase alpha binding pocket, 8 was found to form tight intermolecular contacts, elaborating aphidicolin A8 as a potently cytotoxic lead compound.
