Discovering and harnessing oxidative enzymes for chemoenzymatic synthesis and diversification of anticancer
Tuan-Anh M Nguyen1, Trinh-Don Nguyen1, Yuen Yee Leung1
1Irving K. Barber Faculty of Science, Department of Chemistry, University of British Columbia, 3427 University Way, Kelowna, BC, V1V 1V7, Canada.
Abstract:
Semi-synthetic derivatives of camptothecin, a quinoline alkaloid found in the Camptotheca acuminata tree, are potent anticancer agents. Here we discovered two C. acuminata cytochrome P450 monooxygenases that catalyze regio-specific 10- and 11-oxidations of camptothecin, and demonstrated combinatorial chemoenzymatic C-H functionalizations of the camptothecin scaffold using the new enzymes to produce a suite of anticancer drugs, including topotecan (Hycamtin®) and irinotecan (Camptosar®). This work sheds new light into camptothecin metabolism, and represents greener approaches for accessing clinically relevant camptothecin derivatives.
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