title: Thromboxane A2 receptor antagonism by flavonoids: structure-activity relationships.
abstract: Thromboxane A2 (TxA2) is a strong platelet agonist involved in the pathogenesis of thrombotic diseases that elicits platelet aggregation and vasoconstriction through the activation of its specific membrane receptor (TP). Previous studies have demonstrated that certain flavonoids, naturally occurring phytochemicals, inhibit platelet function through several mechanisms, including antagonism of TP in these cells. However, the steric and inductive or mesomeric requirements underlying this effect are not fully understood. In this study, the ability of 20 naturally occurring flavonoids belonging to different structural subtypes to inhibit [3H]-SQ29548 binding to platelet-rich plasma was compared to establish the structural basis explaining their TP antagonistic activity. The results show a key contribution of C7 and C8 carbons in the A ring, gamma-pyrone structure conjugated with a double bond between C2 and C3 carbons in the C ring, and C2', C3', and C4' carbons in the B ring as the structural determinants that create the active flavonoid skeleton in TP blockade. These data might help in the design of new TP antagonists with potential antithrombotic effects and provide additional evidence for the correlation between biological properties of flavonoids and their structure.
authors.affiliation: Unit of Haematology and Medical Oncology, Centro Regional de Hemodonación, University of Murcia, Murcia, Spain.
authors.forename: Leyre
authors.initials: L
authors.lastname: Navarro-Núñez
authors.forename: Julian
authors.initials: J
authors.lastname: Castillo
authors.forename: María Luisa
authors.initials: ML
authors.lastname: Lozano
authors.forename: Constantino
authors.initials: C
authors.lastname: Martínez
authors.forename: Obdulio
authors.initials: O
authors.lastname: Benavente-García
authors.forename: Vicente
authors.initials: V
authors.lastname: Vicente
authors.forename: Jose
authors.initials: J
authors.lastname: Rivera
mesh_terms: D001792:Blood Platelets / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D005419:Flavonoids / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006834:Hydrazines / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014316:Tritium
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D005419:Flavonoids; D006834:Hydrazines; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D014316:Tritium; C045749:SQ 29548