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The plant-derived natural product parthenolide was recently found to possess potent in vitro and in vivo antitumor activity against leukemia and many other human malignancies.
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Brief Description: The plant-derived natural product parthenolide was recently found to possess potent in vitro and in vivo antitumor activity against leukemia and many other human malignancies, including breast, lung, prostate, liver, brain, pancreas, and bone cancer. This invention describes synthetic methodologies that enable the functionalization of these molecules at positions not readily accessible by previous methods. The inventors discovered that these modifications are beneficial toward improving the anticancer potency and therapeutic index of the molecule. Accordingly, this invention also describes new parthenolide analogs with improved anticancer activity and higher selectivity against tumor cells over normal cells. Advantages: Despite its promise as an anticancer agent, the structural and stereochemical complexity of parthenolide have posed a fundamental obstacle toward its chemical modification and thus its development into a viable drug. This invention describes novel and unique methods useful for modifying (i.e. functionalizing) parthenolide at positions of the molecules which were not previously accessible. Specifically, P450 catalysts are used to oxidize selectively specific positions in the parthenolide scaffold. The oxidized (i.e. hydroxylated) derivatives are then further converted into a variety of semisynthetic analogs. As demonstrated in the invention, this method enables optimization of the pharmacological and drug-like properties of this molecule.