Aphidicolin Chemistry of the Deep-Sea-Derived Fungus Botryotiniafuckeliana MCCC 3A00494

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...