Synthesis of antiplatelet ortho-carbonyl hydroquinones with differential action on platelet aggregation stimulated by collagen or TRAP-6
Author
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Méndez, Diego
Author
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Urra Faúndez, Félix
Author
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Millas Vargas, Juan Pablo
Author
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Alarcón, Marcelo
Author
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Rodríguez Lavado, Julio
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Palomo, Iván
Author
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Trostchansky, Andrés
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Araya Maturana, Ramiro
Author
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Fuentes, Eduardo
Admission date
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2020-05-27T22:51:45Z
Available date
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2020-05-27T22:51:45Z
Publication date
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2020
Cita de ítem
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European Journal of Medicinal Chemistry 192 (2020) 112187
es_ES
Identifier
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10.1016/j.ejmech.2020.112187
Identifier
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https://repositorio.uchile.cl/handle/2250/175047
Abstract
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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.
es_ES
Patrocinador
dc.description.sponsorship
Comisión Nacional de Investigación Científica y Tecnológica (CONICYT).
Comisión Nacional de Investigación Científica y Tecnológica (CONICYT), CONICYT FONDECYT: 1180427, 1180069, 3170813, 3170264.
REDES: 170003, 170002.
PCI: REDBIO0027.
Programa de Investigación Asociativa en Cancer Gástrico: RU2107.
CSIC Grupos: 536.