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Synthesis of antiplatelet ortho-carbonyl hydroquinones with differential action on platelet aggregation stimulated by collagen or TRAP-6.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2020 Apr 15; Vol. 192, pp. 112187. Date of Electronic Publication: 2020 Mar 02. - Publication Year :
- 2020
-
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 (IC <subscript>50</subscript> TRAP-6/IC <subscript>50</subscript> Collagen) and the inhibitory capacity of platelet aggregation. Compounds 3 and 8 inhibit agonist-induced platelet aggregation in a non-competitive manner with IC <subscript>50</subscript> 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.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Cell Survival drug effects
Collagen chemistry
Dose-Response Relationship, Drug
Healthy Volunteers
Humans
Hydroquinones chemical synthesis
Hydroquinones chemistry
Molecular Structure
Peptide Fragments chemistry
Platelet Aggregation Inhibitors chemical synthesis
Platelet Aggregation Inhibitors chemistry
Structure-Activity Relationship
Collagen pharmacology
Hydroquinones pharmacology
Peptide Fragments pharmacology
Platelet Aggregation drug effects
Platelet Aggregation Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 192
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 32155530
- Full Text :
- https://doi.org/10.1016/j.ejmech.2020.112187