Toward Understanding How the Lactone Moiety of Discodermolide Affects Activity

摘要

The potent discodermolide analogues generated in this study have led to a hypothesis that the six-membered ring of discodermolide positions the lactone moiety for a critical interaction within the tubulin binding site. Credence for this hypothesis derives from the sequential removal of functionality from the lactone moiety. On the basis of these observations, a novel butyrolactone analogue has been generated which exhibits improved activity over discodermolide and comprises a significant simplification of the structure. Taken together, these observations could have a significant impact on both the cost and ease of synthesizing a discodermolide derivative as a pharmaceutical.