Epidemiological and clinical trials reveal compelling evidence for the ability of dietary
flavonoids to lower
cardiovascular disease risk. The mechanisms of action of these polyphenolic compounds are diverse, and of particular interest is their ability to function as
protein and
lipid kinase inhibitors. We have previously described structure-activity studies that reinforce the possibility for using
flavonoid structures as templates for
drug design. In the present study, we aim to begin constructing rational screening strategies for exploiting these compounds as templates for the design of clinically relevant,
antiplatelet agents. We used the platelet as a model system to dissect the structural influence of
flavonoids,
stilbenes,
anthocyanidins, and phenolic
acids on inhibition of cell signaling and function. Functional groups identified as relevant for potent inhibition of platelet function included at least 2
benzene rings, a hydroxylated B ring, a planar C ring, a C ring
ketone group, and a C-2 positioned B ring. Hydroxylation of the B ring with either a
catechol group or a single C-4'
hydroxyl may be required for efficient inhibition of
collagen-stimulated
tyrosine phosphorylated
proteins of 125 to 130 kDa, but may not be necessary for that of
phosphotyrosine proteins at approximately 29 kDa. The removal of the C ring C-3
hydroxyl together with a hydroxylated B ring (
apigenin) may confer selectivity for 37 to 38 kDa
phosphotyrosine proteins. We conclude that this study may form the basis for construction of maps of
flavonoid inhibitory activity on
kinase targets that may allow a multitargeted therapeutic approach with analogue counterparts and parent compounds.