Transport mechanisms of a novel antileukemic and antiviral compound 9-norbornyl-6-chloropurine

0443259 - ÚOCHB 2016 RIV GB eng J - Journal Article
Plačková, Pavla - Hřebabecký, Hubert - Šála, Michal - Nencka, Radim - Elbert, Tomáš - Mertlíková-Kaiserová, Helena
Transport mechanisms of a novel antileukemic and antiviral compound 9-norbornyl-6-chloropurine.
Journal of Enzyme Inhibition and Medicinal Chemistry. Roč. 30, č. 1 (2015), s. 57-62. ISSN 1475-6366. E-ISSN 1475-6374
R&D Projects: GA ČR GAP303/11/1297
Institutional support: RVO:61388963
Keywords : carbocyclic nucleoside analogs * CCRF-CEM cells * facilitated diffusion * MRP proteins * P-glycoprotein
Subject RIV: CE - Biochemistry
Impact factor: 3.428, year: 2015

6-Chloropurines substituted at the position 9 with variously modified bicyclic skeletons represent promising antiviral and anticancer agents. This work aimed to investigate the transport mechanisms of 9-[(1R*,2R*,4S*)-bicyclo[2.2.1]hept-2-yl]-6-chloro-9H-purine (9-norbornyl-6-chloropurine, NCP) and their relationship to the metabolism and biological activity of the compound. Transport experiments were conducted in CCRF-CEM cells using radiolabeled compound ([H-3]NCP). The pattern of the intracellular uptake of [H-3]NCP in CCRF-CEM cells pointed to a combination of passive and facilitated diffusion as prevailing transport mechanisms. NCP intracellular metabolism was found to enhance its uptake by modifying NCP concentration gradient. The transport kinetics reached steady state under the conditions of MRP and MDR proteins blockade, indicating that NCP is a substrate for these efflux pumps. Their inhibition also increased the cytotoxicity of NCP. Our findings suggest that the novel nucleoside analog NCP has potential to become a new orally available antileukemic agent due to its rapid membrane permeation.
Permanent Link: http://hdl.handle.net/11104/0246048