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Keywords:

  • antiplatelet drugs;
  • cardiovascular disease;
  • drug design;
  • flavonoids;
  • flavonoid molecular templates;
  • rational screening

Abstract

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.

Practical Application

Human dietary intervention studies show that dietary flavonoids lower cardiovascular disease (CVD) risk. There is a wide range of mechanisms underlying the beneficial effects of these plant chemicals. Of particular interest is their ability to block the function of proteins in cells, as this ability indicates their potential use as templates for the design of drugs. In the present study, we aim to begin constructing strategies for exploiting these compounds as templates for the design of clinically relevant agents applied to treating thrombosis, an important aspect of CVD that leads to heart attacks and stroke.