Synthesis and structure-activity relationships of ticlopidine derivatives and analogs as inhibitors of ectonucleotidase CD39.

Autor: Bi C; PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany., Schäkel L; PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany., Mirza S; PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany., Sylvester K; PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany., Pelletier J; Centre de Recherche du CHU de Québec - Université Laval, Quebec City, QC G1V 4G2, Canada., Lee SY; PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany., Pillaiyar T; PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany., Sévigny J; Centre de Recherche du CHU de Québec - Université Laval, Quebec City, QC G1V 4G2, Canada; Départment de Microbiologie-Infectiologie et d'Immunologie, Faculté de Médecine, Université Laval, Quebec City, QC G1V 0A6, Canada., Müller CE; PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany. Electronic address: christa.mueller@uni-bonn.de.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2023 Jun; Vol. 135, pp. 106460. Date of Electronic Publication: 2023 Mar 11.
DOI: 10.1016/j.bioorg.2023.106460
Abstrakt: Ticlopidine is an antithrombotic prodrug of the thienotetrahydropyridine family. For platelet inhibition it has to undergo oxidative ring-opening by cytochrome P450 enzymes. The resulting thiol reacts with a cysteine residue of the purinergic P2Y 12 receptor on thrombocytes resulting in covalent receptor blockade. Ticlopidine in its intact, not-metabolized form was previously shown to inhibit ecto-nucleoside triphosphate diphosphohydrolase-1 (NTPDase1, also known as cluster of differentiation (CD) 39). CD39 catalyzes the extracellular hydrolysis of ATP via ADP to AMP, which is further hydrolyzed by ecto-5'-nucleotidase (CD73) to adenosine. CD39 inhibition has been proposed as a novel strategy to increase the extracellular concentration of antiproliferative ATP, while decreasing immunosuppressive and cancer-promoting adenosine levels. In the present study, we performed an extensive structure-activity relationship (SAR) analysis of ticlopidine derivatives and analogs as CD39 inhibitors followed by an in-depth characterization of selected compounds. Altogether 74 compounds were synthesized, 41 of which are new, not previously described in literature. Benzotetrahydropyridines, in which the metabolically labile thiophene is replaced by a benzene ring, were discovered as a new class of allosteric CD39 inhibitors.
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.
(Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: