title: Transport mechanisms of a novel antileukemic and antiviral compound 9-norbornyl-6-chloropurine.
abstract: 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 ([(3)H]NCP). The pattern of the intracellular uptake of [(3)H]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.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic , Prague , Czech Republic.
authors.forename: Pavla
authors.initials: P
authors.lastname: Plačková
authors.forename: Hubert
authors.initials: H
authors.lastname: Hřebabecký
authors.forename: Michal
authors.initials: M
authors.lastname: Šála
authors.forename: Radim
authors.initials: R
authors.lastname: Nencka
authors.forename: Tomáš
authors.initials: T
authors.lastname: Elbert
authors.forename: Helena
authors.initials: H
authors.lastname: Mertlíková-Kaiserová
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D004976:Ethacrynic Acid / Q000494:pharmacology; D055459:Facilitated Diffusion; D015870:Gene Expression; D006801:Humans; D007700:Kinetics; D011422:Propionates / Q000494:pharmacology; D011687:Purines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014316:Tritium
chemical_list: C583750:9-norbornyl-6-chloropurine; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D003986:Dibenzocycloheptenes; D011422:Propionates; D011687:Purines; D011804:Quinolines; D014316:Tritium; D019328:Buthionine Sulfoximine; C059141:verlukast; C095179:zosuquidar trihydrochloride; D004976:Ethacrynic Acid
keywords: CCRF-CEM cells; Carbocyclic nucleoside analogs; MRP proteins; P-glycoprotein; facilitated diffusion