Insights into dietary flavonoids as molecular templates for the design of anti-platelet drugs

Abstract

Flavonoids are low-molecular weight, aromatic compounds derived from fruits, vegetables, and other plant components. The consumption of these phytochemicals has been reported to be associated with reduced cardiovascular disease (CVD) risk, attributed to their anti-inflammatory, anti-proliferative, and anti-thrombotic actions. Flavonoids exert these effects by a number of mechanisms which include attenuation of kinase activity mediated at the cell-receptor level and/or within cells, and are characterized as broad-spectrum kinase inhibitors. Therefore, flavonoid therapy for CVD is potentially complex; the use of these compounds as molecular templates for the design of selective and potent small-molecule inhibitors may be a simpler approach to treat this condition. Flavonoids as templates for drug design are, however, poorly exploited despite the development of analogues based on the flavonol, isoflavonone, and isoflavanone subgroups. Further exploitation of this family of compounds is warranted due to a structural diversity that presents great scope for creating novel kinase inhibitors. The use of computational methodologies to define the flavonoid pharmacophore together with biological investigations of their effects on kinase activity, in appropriate cellular systems, is the current approach to characterize key structural features that will inform drug design. This focussed review highlights the potential of flavonoids to guide the design of clinically safer, more selective, and potent small-molecule inhibitors of cell signalling, applicable to anti-platelet therapy.

Figure 1

Inhibition of platelet signalling by flavonoids. Flavonoids inhibit tyrosine kinases (Src, Fyn, Lyn, Hck, Syk), lipid kinases (PI3K), and serine/threonine kinases (PKC) and phospholipases (PLCγ2) involved in inside-out signalling (that initiates platelet activation) and outside-in signalling (that maintains platelet activation). These compounds also inhibit by targeting calcium signalling that is essential for platelet activation, they potentially disrupt fibrinogen and collagen binding to integrin α_IIbβ₃ and GPVI, respectively, and it is likely that they perturb the platelet plasma membrane.

Figure 2

The structures of polyphenol compounds. Flavonoids form a major subgroup of the polyphenol family of compounds and include flavonols, flavones, flavan-3-ols, phenolic acids, isoflavones, and stilbenes. Flavones (chrysin, apigenin) are characterized by a non-hydroxylated C ring, whereas flavonol (galangin, kaempferol, quercetin, myricetin) C rings contain a C-3 hydroxyl group. Flavononols (taxifolin) are flavonols with a non-planar C ring. Flavan-3-ols (catechin) are defined by a non-planar, C-3 hydroxylated C ring that is not substituted with a C-4 carbonyl group and flavonones (naringenin) are defined by a non-planar, non-hydroxylated C ring containing a carbonyl group. Stilbenes (resveratrol) are characterized by 2 hydroxylated benzene rings in cis or trans conformations and the isoflavones (genistein) are defined by a B ring substituted to the C3 position on the C ring. Cyanidins (cyanidin) are defined by a positively charged C ring, and phenolic acids (caffeic acid and gallic acid) are benzene rings substituted with carboxyl and hydroxyl groups.

Figure 3

Flavonoid analogues. Analogues based on quercetin (LY294002 and quercetin-3-O-amino-esters) and the flavonoid chromone moeity (5-cyclohexylmethoxy-3-(4-hydroxybenzyl)-4H-chromen-4-one).