2. Academic Validation
  3. Synthesis of antiplatelet ortho-carbonyl hydroquinones with differential action on platelet aggregation stimulated by collagen or TRAP-6

Synthesis of antiplatelet ortho-carbonyl hydroquinones with differential action on platelet aggregation stimulated by collagen or TRAP-6

  • Eur J Med Chem. 2020 Apr 15;192:112187. doi: 10.1016/j.ejmech.2020.112187.
Diego Méndez 1,  Félix A Urra 2,  Juan Pablo Millas-Vargas 3,  Marcelo Alarcón 1,  Julio Rodríguez-Lavado 4,  Iván Palomo 1,  Andrés Trostchansky 5,  Ramiro Araya-Maturana 6,  Eduardo Fuentes 7
Affiliations

Affiliations

  • 1 Thrombosis Research Center, Medical Technology School, Department of Clinical Biochemistry and Immunohaematology, Faculty of Health Sciences, Universidad de Talca, Talca, Chile.
  • 2 Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile; Network for Snake Venom Research and Drug Discovery, Santiago, Chile. Electronic address: felixurraf@u.uchile.cl.
  • 3 Instituto de Química de Recursos Naturales, Programa de Investigación Asociativa en Cáncer Gástrico (PIA-CG), Universidad de Talca, Talca, Chile.
  • 4 Departamento de Química Orgánica y Fisicoquímica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
  • 5 Departamento de Bioquímica and Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
  • 6 Thrombosis Research Center, Medical Technology School, Department of Clinical Biochemistry and Immunohaematology, Faculty of Health Sciences, Universidad de Talca, Talca, Chile; Instituto de Química de Recursos Naturales, Programa de Investigación Asociativa en Cáncer Gástrico (PIA-CG), Universidad de Talca, Talca, Chile; Network for Snake Venom Research and Drug Discovery, Santiago, Chile. Electronic address: raraya@utalca.cl.
  • 7 Thrombosis Research Center, Medical Technology School, Department of Clinical Biochemistry and Immunohaematology, Faculty of Health Sciences, Universidad de Talca, Talca, Chile. Electronic address: edfuentes@utalca.cl.
PMID: 32155530 DOI: 10.1016/j.ejmech.2020.112187
Abstract

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 μM (collagen) and 11.88 ± 4.59 μM (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.

Keywords

Hydroquinone derivatives; Ortho-carbonyl; Platelets; Small molecules; Thrombosis.

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