Potent Inhibitors of Phosphatidylinositol 3 (PI3) Kinase that have Antiproliferative Activity Only When Delivered as Prodrug Forms

Prodrugs for PI3K: A series of substituted analogues of the phosphatidylinositol 3 kinase (PI3K) inhibitor LY294002 were prepared and found to potently inhibit the isolated enzyme but not MCF7 cell proliferation. Two tetrazolyl‐substituted analogues were further derivatized as prodrugs resulting in restoration of cell‐based activity. These data provide a conceptual model for development of tumor‐targeting prodrug forms of cell‐impermeable PI3K inhibitors.