American Chemical Society
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Aphidicolin Chemistry of the Deep-Sea-Derived Fungus Botryotinia fuckeliana MCCC 3A00494

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posted on 2019-08-12, 18:05 authored by Siwen Niu, Jin-Mei Xia, Zengpeng Li, Long-He Yang, Zhi-Wei Yi, Chun-Lan Xie, Guizhen Peng, Zhu-Hua Luo, Zongze Shao, Xian-Wen Yang
Aphidicolin, a potent DNA polymerase α 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 A1–A71, 171) and eight known (7279) aphidicolin congeners from Botryotinia fuckeliana MCCC 3A00494, a fungus isolated from the western Pacific Ocean (−5572 m). The structures of 171 were determined through extensive spectroscopic analysis, X-ray crystallography, chemical derivatization, modified Mosher’s method, and the ECD exciton chirality method. Compounds 5457 and 5864 are novel 6/6/5/6/5 pentacyclic aphidicolins featuring tetrahydrofuran and dihydrofuran rings, respectively, while compounds 6571 are rare noraphidicolins. Aphidicolin A8 (8) significantly induced apoptosis in T24 (IC50 = 2.5 μM) and HL-60 (IC50 = 6.1 μM) cancer cells by causing DNA damage. By docking its structure to the human DNA polymerase α binding pocket, 8 was found to form tight intermolecular contacts, elaborating aphidicolin A8 as a potently cytotoxic lead compound.