New analogues of 13-hydroxyocatdecadienoic acid and 12-hydroxyeicosatetraenoic acid block human blood platelet aggregation and cyclooxygenase-1 activity

Chemistry Central Journal

Taghreed Hirz²  Ali Khalaf⁵  Nehme El-Hachem²  May F Mrad²  Hassan Abdallah¹  Christophe Créminon⁴  René Grée⁵  Raghida Abou Merhi³  Aïda Habib²  Ali Hachem¹  Eva Hamade³ 

[1] Département de Chimie et de Biochimie, Laboratoire de Chimie Médicinale et des Produits Naturels & PRASE, EDST Lebanese University, Hadath, Lebanon

[2] Department of Biochemistry and Molecular Genetics, Faculty of Medicine, AUB, Beirut, POBox 11–236, Lebanon

[3] Génomique et Santé, Lebanese University, Hadath, Lebanon

[4] iBiTec-S, Service de pharmacologie et d’immuno analyse, CEA Saclay - Bât. 532, 91191, Gif-Sur-Yvette cedex, France

[5] Institut des Sciences Chimiques de Rennes, Université de Rennes 1, CNRS UMR 6226, Avenue du Général Leclerc, 35042, Rennes Cedex, France

关键词: Thrombosis;    Polyunsaturated fatty acid;    Inhibitors;    Anti-thrombotic;    Cyclooxygenase-1;   

Others  :  788003
DOI  :  10.1186/1752-153X-6-152

 received in 2012-09-24, accepted in 2012-12-03,  发布年份 2012

【 摘 要 】

Background

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.

Conclusions

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.

【 授权许可】

   
2012 Hirz et al.; licensee Chemistry Central Ltd.

【 图 表 】

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