Synthesis and structure-activity relationships of ticlopidine derivatives and analogs as inhibitors of ectonucleotidase CD39
Bioorganic chemistry(2023)
摘要
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 P2Y12 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.
更多查看译文
关键词
CD39 inhibitors,NTPDases,NTPDase1-2-3-8,Synthesis,Thienotetrahydropyridine,Tetrahydroisoquinoline,Ticlopidine,Inflammation,Immunotherapy
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要