Impact of specific functional groups in flavonoids on the modulation of platelet activation

Abstract

Flavonoids exert innumerable beneficial effects on cardiovascular health including the reduction of platelet activation, and thereby, thrombosis. Hence, flavonoids are deemed to be a molecular template for the design of novel therapeutic agents for various diseases including thrombotic conditions. However, the structure-activity relationships of flavonoids with platelets is not fully understood. Therefore, this study aims to advance the current knowledge on structure-activity relationships of flavonoids through a systematic analysis of structurally-related flavones. Here, we investigated a panel of 16 synthetic flavones containing hydroxy or methoxy groups at C-7,8 positions on the A-ring, with a phenyl group or its bioisosteres as the B-ring, along with their thio analogues possessing a sulfur molecule at the 4th carbon position of the C-ring. The antiplatelet efficacies of these compounds were analysed using human isolated platelets upon activation with cross-linked collagen-related peptide by optical aggregometry. The results demonstrate that the hydroxyl groups in flavonoids are important for optimum platelet inhibitory activities. In addition, the 4-C=O and B ring phenyl groups are less critical for the antiplatelet activity of these flavonoids. This structure-activity relationship of flavonoids with the modulation of platelet function may guide the design, optimisation and development of flavonoid scaffolds as antiplatelet agents.

The endogenous antimicrobial cathelicidin LL37 induces platelet activation and augments thrombus formation

“…To determine whether LL37 has a direct influence on thrombotic complications during inflammatory diseases, its effects on thrombus formation under arterial flow conditions were investigated. 26,27 LL37 (10, 20, and 50 mM) significantly increased the thrombus formation ( Figure 1Di) and the mean fluorescence intensity in a concentration-dependent manner (Figure 1Dii). The highest concentration of LL37 (50 mM) increased the thrombus intensity by ;70% compared with the vehicle-treated samples (Figure 1Diii).…”

Synthetic Flavonoids as Novel Modulators of Platelet Function and Thrombosis

“…Del Turco et al [59] developed multiple synthetic 2,3-diphenyl-4 H -pyrido(1,2-α)pyrimidin-4-one flavonoids and discovered that two of these compounds with multiple methoxy groups (Compound 6 (Figure 2G) and Compound 7 (Figure 2H)) were more potent than either quercetin or apigenin in response to the activation of PRP by collagen or U46619 [59].…”

“…3′,4′-Dihydroxyflavonol (DiOHF; a modified form of quercetin; Figure 2N) decreases murine PRP aggregation in response to a PAR4 agonist whether administered in a single IV bolus (47.0 ± 4.0% versus 57.6 ± 6.1%) or IP over the period of a week (50.4 ± 6.6% versus 73.4 ± 4.6%) [39,62]. Synthetic flavonoids that have been proposed to act as TP receptor antagonists are ineffective at inhibiting thrombin-induced platelet aggregation [59]. Despite Ru-thiochrysin imparting a greater effect on plasma proteins ex vivo , no significant difference between the tail bleeding times of mice treated with chrysin or Ru-thiochrysin was seen at the same concentration, which also emphasised this as a safer compound for therapeutic applications [57].…”

“…Both chrysin and Ru-thiochrysin inhibit dense- and α-granule secretion; however, Ru-thiochrysin inhibits P-selectin exposure more than chrysin, yet there were no significant differences between their effects on dense granule secretion [57]. Other synthetic flavonoids such as 2,3-diphenyl-4 H -pyrido(1,2-α)pyrimidin-4-one flavonoids decrease α-granule secretion induced by U46619 [59]. Conversely, PAR4-mediated dense granule secretion was inhibited by DiOHF but with the same efficacy as quercetin; meanwhile, α-granule secretion was unaffected by either compound [39].…”

“…Limited studies have investigated the ligation of synthetic flavonoids to specific molecular targets on the surface of platelets. Naturally occurring flavonoids have been suggested to have extracellular targets and 2,3-diphenyl-4H-pyrido(1,2-α)pyrimidin-4-one flavonoids, like apigenin, have been shown to antagonise TP receptor [22,59].…”