Synthesis of Uscharin Oxime Analogues and Their Biological Evaluation as HIF-1 Inhibitors

Uscharin-like non-classical cardenolides are considered to be useful as HIF-1 inhibitors in the treatment of cancers. To develop more potent HIF-1 inhibitors, oximes and oxime ethers of uscharin were designed and synthesized. Oximation of uscharin exhibited unexpectedly a regioselectivity and stereoselectivity at 3 '-thiazoline but not at the 19-aldehyde group, since either E-ketoxime derivative 2 or its ether 5 at C-3 ' was found as the only product during oximation of uscharin using hydroxylamine or methoxyamine at room temperature. Two 19-aldoxime derivatives 4 and 6 were also synthesized. Ketoxime analogue 2 showed more potent inhibitory effect on HIF-1 transcriptional activity than the parental uscharin. Ketoxime ether 5 and 19-aldoxime 6 exhibited stronger HIF-1 suppressing effect than digoxin (the positive control drug). Moreover, ketoxime derivative 2 displayed the most potent anti-proliferative activity against MCF-7 cancer cells among all compounds. An analysis of structure-activity relationship revealed that 3 '-ketoxime is a superior moiety to a thiazoline ring, while 19-aldoxime is inferior to an aldehyde counterpart. Our findings may provide some guidance for the rational design of uscharin-based promising HIF-1 inhibitors.