期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 192, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2020.112187
关键词
Hydroquinone derivatives; Ortho-carbonyl; Platelets; Thrombosis; Small molecules
资金
- CONICYT
- FONDECYT [1180427, 1180069, 3170813, 3170264]
- REDES [170003, 170002]
- PCI [REDBIO0027]
- Programa de Investigacion Asociativa en Cancer Gastrico [RU2107]
- CSIC Grupos [536]
Cardiovascular diseases are the leading cause of death in the world. Platelets have a major role in cardiovascular events as they bind to the damaged endothelium activating and forming thrombi. Although some hydroquinone scaffold-containing compounds have known antiplatelet activities, currently there is a lack of evidence on the antiplatelet activity of hydroquinones carrying electron attractor groups. In this work, we evaluate the antiplatelet effect of a series of ortho-carbonyl hydroquinone derivatives on cytotoxicity and function of human platelets, using collagen and thrombin receptor activator peptide 6 (TRAP-6) as agonists. Our structure-activity relationship study shows that gem-diethyl/methyl substitutions and the addition/modifications of the third ring of ortho-carbonyl hydroquinone scaffold influence on the selective index (IC50 TRAP-6/IC50 Collagen) and the inhibitory capacity of platelet aggregation. Compounds 3 and 8 inhibit agonist-induced platelet aggregation in a non-competitive manner with IC50 values of 1.77 +/- 2.09 mu M (collagen) and 11.88 +/- 4.59 mu M (TRAP-6), respectively and show no cytotoxicity. Both compounds do not affect intracellular calcium levels and mitochondrial bioenergetics. Consistently, they reduce the expression of P-selectin, activation of glycoprotein IIb/IIIa, and release of adenosine triphosphate and CD63 from platelet. Our findings may be used for further development of new drugs in platelet-related thrombosis diseases. (c) 2020 Elsevier Masson SAS. All rights reserved.
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