title: Investigating flavonoids as molecular templates for the design of small-molecule inhibitors of cell signaling.
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.
authors: Inst. for Cardiovascular and Metabolic Research (ICMR), School of Biological Sciences, Univ. of Reading, Reading, RG6 6UB Berkshire, U.K.
authors: Bernice
authors: B
authors: Wright
authors: Marcus J
authors: MJ
authors: Tindall
authors: Julie A
authors: JA
authors: Lovegrove
authors: Jonathan M
authors: JM
authors: Gibbins
mesh_terms: D000872:Anthocyanins / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects*; D002318:Cardiovascular Diseases / Q000517:prevention & control; D015195:Drug Design; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D062385:Hydroxybenzoates / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D059808:Polyphenols / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013267:Stilbenes / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000872:Anthocyanins; D005419:Flavonoids; D062385:Hydroxybenzoates; D010975:Platelet Aggregation Inhibitors; D059808:Polyphenols; D013267:Stilbenes; C017616:phenolic acid
keywords: antiplatelet drugs; cardiovascular disease; drug design; flavonoid molecular templates; flavonoids; rational screening