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Aphidicolin Chemistry of the Deep-Sea-Derived Fungus

Aphidicolin Chemistry of the Deep-Sea-Derived Fungus

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

J Nat Prod. 2019 Aug 23;82(8):2307-2331.

PMID: 31403790

Abstract:

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, 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 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP38966211-A	Aphidicolin		38966-21-1	Price

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