Natural products are a major source of therapeutic agents, but modification of these molecules is often critical for improving their pharmacological properties as drug candidates. Our group has pioneered the use of chemoenzymatic synthesis using engineered P450 enzymes for the late-stage functionalization of complex molecules such as natural products. Using this strategy, a P450 enzyme was developed for the regio- and stereoselective hydroxylation of micheliolide (MCL). These enzymes were leveraged to produce a panel of novel micheliolide analogs via late-stage enzymatic hydroxylation, followed by azidation and azide/alkyne cycloaddition reactions. These compounds were tested for antileukemic and anticancer properties <i>in vitro, </i>resulting in the identification of MCL analogs with distinct anticancer profiles as well as analogs with enhanced (2-8-fold) antileukemic and anticancer activity compared to the parent natural product. These analyses identified MCL analogs with general and selective anticancer properties that provide insight for the future design of other modified natural products.

Development and investigation of micheliolide-based anticancer agents via late-stage chemoenzymatic C – H functionalization

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