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Nguyen, Minh Tuan Anh

University of British Columbia

Since the 1990s, topotecan and irinotecan, two camptothecin derivatives, have been widely used as anticancer drugs owing to their phenomenal topoisomerase-I inhibitory activity. In the pharmaceutical industry, topotecan and irinotecan are chemically synthesized from the prodrug camptothecin, a quinoline alkaloid from Camptotheca acuminata, via 10-hydroxycamptothecin (10-HCPT), using toxic reagents and harsh conditions. This project aims to develop a chemoenzymatic approach for 10-HCPT production by exploring its biosynthetic pathway in C. acuminata. Multidisciplinary techniques, including bioinformatics, molecular cloning, and organic synthesis, were implemented to discover and characterize the plant metabolic enzymes. Two cytochrome P450 monooxygenases have been discovered that regio-selectively hydroxylated camptothecin at two different positions, C-10 and C-11 on the CPT scaffold. The high regio-selectivity and conversion rate (12 mg/L – biotransformation rate) afford the production of hydroxycamptothecins (10/11-HCPT) in the baker’s yeast Saccharomyces cerevisiae. By combining cytochrome P450 enzymes and chemo-catalysts sequentially in the chemoenzymatic process, 13 camptothecin derivatives including topotecan and irinotecan have been successfully synthesized. This research is a step forward in camptothecin biochemistry and leading finally to the economical and sustainable production of more active and water-soluble camptothecin derivatives.

Text

2022-09-07

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/80154

Chemistry

University of British Columbia

UBCO

http://creativecommons.org/licenses/by-nc-nd/4.0/