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

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 f uckeliana MCCC 3A00494, a fungus isolated from the western Pacific Ocean (−5572 m). The structures of 1−71 were determined through extensive spectroscopic analysis, Xray 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 (IC 50 = 2.5 μM) and HL-60 (IC 50 = 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.

Novel Marine Secondary Metabolites Worthy of Development as Anticancer Agents: A Review

“…With the docking of its molecular structure to the human DNA polymerase alpha binding pocket, Cpd. 183 formed tight intermolecular contacts, substantiating aphidicolin A8 as a potent cytotoxic lead compound [ 58 ].…”

A New Pimarane Diterpenoid from the Botryotinia fuckeliana Fungus Isolated from Deep‐Sea Water

“…The fungus B. fuckeliana MCCC 3A00494 was obtained from the deep‐sea water at a depth of 5572 m by sampling from the western Pacific Ocean. For the fungal identification and large‐scale fermentation procedure, see our recently published literature …”

“…Pimarane diterpenoids have attracted much attentions of chemists and pharmacologists because many of them featured a broad spectrum of biological activities, for example cytotoxic, antibacterial, anti‐inflammatory, TRAIL‐resistance‐overcoming, and Candida albicans morphogenesis inhibitory activities . The fungus Botryotinia fuckeliana MCCC 3A00494 was obtained from the deep‐sea water by sampling from the western Pacific Ocean at a depth of 5572 m, from which we isolated 71 new and eight known aphidicolin diterpenoids . Further investigation on this fungus resulted in the isolation of one new pimarane diterpenoid botryopimarene A ( 1 ) and 10 known compounds 2 – 11 ( Figure ).…”

Bioactive Metabolites from the Deep-Sea-Derived Fungus Diaporthe longicolla FS429

“…After that, there was no further research about the chemical investigation of deep-sea-derived fungi until 1996, when Cui and his co-worker isolated two novel diketopiperazine derivatives spirotryprostatins A and B from Aspergillus funigatus [ 4 ]. Since then, the deep-sea-derived fungi have attracted more and more attention due to their abundant secondary metabolites [ 2 ], for example, 71 new aphidicolins were recently isolated from the deep-sea-derived Botryotinia fuckeliana [ 5 ]. Moreover, according to literature surveys, approximately 80% of the compounds exhibited potential bioactivities and more than half of them, including compounds such as aspeterreurone A [ 6 ], botryotins A–H [ 7 ] and penixylarins A–D [ 8 ], show cytotoxicity against different human cancer cell lines.…”