We have recently shown that the steroidal lactone, withaferin A (WA), isolated from the Indian medicinal plant, Withania somnifera, to be the first small molecule natural product found to bind covalently to the enigmatic adapter protein, annexin II, and exhibit both in vitro and in vivo anticancer activity.1 Significant in vivo anticancer activity of WA and its novel mechanism of action prompted us to undertake a preliminary SAR study of this compound. Starting from WA we have synthesized eight of its analogs and evaluated them in assays for heat shock induction, cell migration inhibition, and angiogenesis. Results obtained in these studies thus far suggest the importance of some structural features of WA for its observed biological activity.

1Falsey, R. R.; Marron, M. T.; Gunaherath, G. M. K. B.; Shirahatti, N.; Mahadevan, D.; Gunatilaka, A. A. L.; Whitesell, L, Nature Chemical Biology, 2006, 2, 33-38.