New analogues of 13-hydroxyocatdecadienoic acid and 12-hydroxyeicosatetraenoic acid block human blood platelet aggregation and cyclooxygenase-1 activity
- Equal contributors
1 Department of Biochemistry and Molecular Genetics, Faculty of Medicine, AUB, Beirut, POBox 11–236, Lebanon
2 Département de Chimie et de Biochimie, Laboratoire de Chimie Médicinale et des Produits Naturels & PRASE, EDST Lebanese University, Hadath, Lebanon
3 Institut des Sciences Chimiques de Rennes, Université de Rennes 1, CNRS UMR 6226, Avenue du Général Leclerc, 35042, Rennes Cedex, France
4 iBiTec-S, Service de pharmacologie et d’immuno analyse, CEA Saclay - Bât. 532, 91191, Gif-Sur-Yvette cedex, France
5 Génomique et Santé, Lebanese University, Hadath, Lebanon
Chemistry Central Journal 2012, 6:152 doi:10.1186/1752-153X-6-152Published: 10 December 2012
Thromboxane A2 is derived from arachidonic acid through the action of cyclooxygenases and thromboxane synthase. It is mainly formed in blood platelets upon activation and plays an important role in aggregation. Aspirin is effective in reducing the incidence of complications following acute coronary syndrome and stroke. The anti-thrombotic effect of aspirin is obtained through the irreversible inhibition of cyclooxygenases. Analogues of 12-hydroxyeicosatetraenoic acid and 13-hydroxyocatdecadienoic acid were shown previously to modulate platelet activation and to block thromboxane receptors.
Results and discussion
We synthesized 10 compounds based on the structures of analogues of 12-hydroxyeicosatetraenoic acid and 13-hydroxyocatdecadienoic acid and evaluated their effect on platelet aggregation triggered by arachidonic acid. The structure activity relationship was evaluated. Five compounds showed a significant inhibition of platelet aggregation and highlighted the importance of the lipidic hydrophobic hydrocarbon chain and the phenol group. Their IC50 ranged from 7.5 ± 0.8 to 14.2 ± 5.7 μM (Mean ± S.E.M.). All five compounds decreased platelet aggregation and thromboxane synthesis in response to collagen whereas no modification of platelet aggregation in response to thromboxane receptor agonist, U46619, was observed. Using COS-7 cells overexpressing human cyclooxygenase-1, we showed that these compounds are specific inhibitors of cyclooxygenase-1 with IC50 ranging from 1.3 to 12 μM. Docking observation of human recombinant cyclooxygenase-1 supported a role of the phenol group in the fitting of cyclooxygenase-1, most likely related to hydrogen bonding with the Tyr 355 of cyclooxygenase-1.
In conclusion, the compounds we synthesized at first based on the structures of analogues of 12 lipoxygenase metabolites showed a role of the phenol group in the anti-platelet and anti-cyclooxygenase-1 activities. These compounds mediate their effects via blockade of cyclooxygenase-1.