title: Nitrooxyacyl derivatives of salicylic acid: aspirin-like molecules that covalently inactivate cyclooxygenase-1.
abstract: A recently described series of nitrooxyacyl derivatives of salicylic acid, displaying aspirin-like anti-inflammatory and platelet anti-aggregatory properties, were evaluated for their abilities to inhibit cyclooxygenase (COX). A number of these compounds irreversibly inhibited both COX-1 and COX-2 isoforms when tested in isolated human platelets and monocytes. Further studies using COX-1 expressed in human HEK293T cells showed that this inhibition mechanism is similar to that of aspirin; namely, the products are able to covalently bind to the Ser 530 residue present in the active cleft of the enzyme. Molecular modeling enabled us to rationalize this behavior. Because these products were previously found to display NO-dependent properties in rat animal models, particularly as they decreased in vivo gastrotoxicity and induced in vitro vasodilation, they represent a new and interesting class of potential aspirin-like antithrombotic agents worthy of further study.
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Pietro Giuria 9, 10125 Torino, Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: Cena
authors.forename: Paolo
authors.initials: P
authors.lastname: Tosco
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Marini
authors.forename: Loretta
authors.initials: L
authors.lastname: Lazzarato
authors.forename: Marco
authors.initials: M
authors.lastname: Piccinini
authors.forename: Cristina
authors.initials: C
authors.lastname: Ramondetti
authors.forename: Elisa
authors.initials: E
authors.lastname: Lupino
authors.forename: Roberta
authors.initials: R
authors.lastname: Fruttero
authors.forename: Alberto
authors.initials: A
authors.lastname: Gasco
mesh_terms: D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001241:Aspirin / Q000737:chemistry; D020134:Catalytic Domain; D002460:Cell Line; D003198:Computer Simulation; D051545:Cyclooxygenase 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020156:Salicylic Acid / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011994:Recombinant Proteins; D051545:Cyclooxygenase 1; D020156:Salicylic Acid; D001241:Aspirin