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.
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