Abstract
BackgroundThromboxane 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 discussionWe 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.ConclusionsIn 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.
Highlights
Thromboxane A2 is derived from arachidonic acid through the action of cyclooxygenases and thromboxane synthase
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
We have previously reported that stabilized analogues of 13- HODE and 12- HETE have inhibitory effects on TX –dependent platelet aggregation [14]
Summary
Chemistry Compounds 1 and 2 were obtained by removing the lipophilic chain with the carboxylic acid directly linked to the aromatic group (compound 2) or replacing it by an oxime (compound 1). Compounds 1 and 2 had a shorter hydrophilic carbonic chain compared to analogue A (Figure 1 and Scheme 1) and showed no inhibitory effect on arachidonic acid-dependent platelet aggregation (Table 1). The IC50 of type II compounds were compared with ibuprofen (Table 1) We conclude from these results that for type I molecules the hydroxyl group at R1 position is critical for the inhibitory effect and that the length of the R3 hydrocarbon chain is appropriate between 4 and 5 carbons, as described for compounds. None of the compounds 3, 4, 7, 8 and 9 were able to act on the thromboxane receptor- dependent platelet aggregation in response to 1 μM of U46619, an agonist of the thromboxane receptor (Figure 7) Overall, these results, along with the effect on arachidonic acid- dependent platelet aggregation and on human recombinant COX-1, support that these new molecules affect platelet aggregation via inhibition of TX formation. Blocking this –OH interfered with the biological activity of these inhibitors
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