The selective activation of aliphatic C-H bonds in complex organic molecules via engineered cytochromes P450 is a promising approach for the late stage diversification of natural products. This report describes the use of P450 'fingerprinting' as a method to rapidly identify P450 catalysts capable of selective oxidation of parthenolide, a sesquiterpene lactone with attractive anticancer properties. Further chemical modification of the oxidized derivatives via acylation chemistry allowed for the generation of a novel class of parthenolide derivatives with improved activity against acute myelogenous leukemia. This method highlights the use of engineered cytochrome P450s and P450-mediated chemoenzymatic synthesis as a valuable strategy to enable the derivatization and exploration of complex natural product scaffolds.

Late-stage functionalization of anticancer natural product parthenolide via engineered P450 catalysts

247th National Meeting (2014)

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