RELATIONSHIP BETWEEN FLAVONOID STRUCTURE AND INHIBITION OF PHOSPHATIDYLINOSITOL 3-KINASE - A COMPARISON WITH TYROSINE KINASE AND PROTEIN-KINASE-C INHIBITION

Depending on their structure, flavonoids display more or less potent i nhibitory effects on the growth and proliferation of certain malignant cells in vitro, and these effects are thought re, be due to inhibitio n of various enzymes. We investigated the inhibitory action of fourtee n flavonoids of different chemical classes on phosphatidylinositol 3-k inase alpha (PI 3-kinase alpha) activity, an enzyme recently shown to play an important role in signal transduction and cell transformation. Of the fourteen flavonoids tested, myricetin was the most potent PI 3 -kinase inhibitor (IC50 = 1.8 mu M), while luteolin and apigenin were also effective inhibitors, with IC50 values of 8 and 12 mu M, respecti vely. Fisetin and quercetin, as previously reported, were also found t o significantly inhibit PI 3-kinase activity. The same flavonoids were also analyzed for inhibition of epidermal growth factor receptor (EGF -R), intrinsic tyrosine kinase and bovine brain protein kinase C (PKC) . At elevated doses, some of these flavonoids were found to also cause significant inhibition of PKC and tyrosine kinase activity of EGF-R. A structure-activity study indicated that the position, number and sub stitution of the hydroxyl group of the B ring, and saturation of the C 2-C3 bond are important factors affecting flavonoid inhibition of PI 3 -kinase. They may also play a significant role in specificity of inhib ition and could help to provide a basis for the further design of spec ific inhibitors of this lipid kinase. Finally, possible relationships between the antitumoral properties of these flavonoids and their biolo gical activities are discussed. BIOCHEM PHARMACOL 53;11:1649-1657, 199 7. (C) 1997 Elsevier Science Inc.