Jürgen Rohr, Madan K. Kharel, Micah Shepherd, Tao Liu, and Eric Nybo. College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, KY 40536
The gilvocarcins represent the most potent group of the benzo[d]naphtho[1,2-b]pyran-6-one C-glycoside anticancer antibiotics. For their mechanisms of action, a crosslinking between DNA and histone H3 was suggested, for which two structural elements are crucial, namely the vinyl group in 8-position and the C-glycosidic moiety in 4-position. The closely related anticancer drugs ravidomycin and chrysomycin differ from gilvocarcin V only in their deoxysugar moieties, indicating that nature provided some ‘spiel’ in this region to allow for further improvement of biological activity. Our recent research focused on the biosynthetic key enzymes responsible for the generation of the two crucial structural moieties, namely the enzymes that establish the vinyl side chain and the enzymes responsible for the formation of the sugar moieties and the C-glycosidic connection. Both, the understanding of these enzymes and their manipulation are important for the future generation of novel gilvocarcin analogues by combinatorial biosynthesis.
