Synthesis and Activity of C11-Modified Wortmannin Probes for PI3 Kinase

Abstract

The key role played by PI3 kinase in cancer, hormone action, and a host of other biological functions suggests that specific inhibitors whose disposition could be ascertained in vivo would be useful in biological research or, potentially, for imaging PI3K in a clinical setting. Wortmannin (Win, 1) is an inhibitor of PI3 kinase with high specificity for this enzyme. We synthesized three modified Win probes, a biotinylated Win (7a), a 4-hydroxy-3-iodophenylated Win, which was obtained both unlabeled (7b) and labeled with I-125(8), and a fluoresceinated Win (7c), through modification at C-11, and evaluated their inhibitive activity as inhibitors of PI3 kinase. Biotinylated (7a) and 4-hydroxy-3-iodophenylated Win's (7b) had IC(50)s for PI3K of 6.11 and 11.02 nM, respectively, compared to an IC50 for Win of 1.63 nM. Fluoresceinated Win (7c) lost considerably more activity than the other derivatives, with an IC50 of 64.9 nM. The I-125 labeled 4-hydroxy-3-iodophenylated Win (8) could be detected after reaction with an immunoprecipitate of PI3 kinase. The activity of these reporter Win's is discussed in relationship to earlier findings on the pharmacological activity of Win derivatives and the ability of inhibitors to fit into the ATP pocket of PI3 kinase.