Aphidicolin Chemistry of the Deep-Sea-Derived Fungus Botryotinia fuckeliana MCCC 3A00494
- J Nat Prod. 2019 Aug 23;82(8):2307-2331. doi: 10.1021/acs.jnatprod.9b00705.
- 1. State Key Laboratory Breeding Base of Marine Genetic Resources, Key Laboratory of Marine Genetic Resources, Fujian Key Laboratory of Marine Genetic Resources, South China Sea Bio-Resource Exploitation and Utilization Collaborative Innovation Center , Third Institute of Oceanography, Ministry of Natural Resources , 184 Daxue Road , Xiamen 361005 , People's Republic of China.
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.