[摘要]：When the viridin wortmannin (Wm) is modified by reaction with certain nucleophiles at the C20 position, the compds. obtained exhibit an improved antiproliferative activity even though a covalent reaction between C20 and a lysine in the active site of PI3 kinase is essential to Wm's ability to inhibit this enzyme. Here the authors show that this improved potency results from an intramol. attack by the C6 hydroxyl group that slowly converts these inactive prodrugs to the active species Wm over the 48 h duration of the antiproliferative assay. The results provide a guide for selecting Wm-like compds. to maximize kinase inhibition with the variety of protocols used to assess the role of PI3 kinase in biol. systems, or for achieving optimal therapeutic effects in vivo. In addn., the slow self-activation of WmC20 derivs. provides a mechanism that can be exploited to obtain kinase inhibitors endowed with phys. and pharmacokinetic properties far different from man-made kinase inhibitors because they do not bind to kinase active sites.
