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.

Recent Experimental Developments in Studying Passive Membrane Transport of Drug Molecules

“…301 However, 3 H-antileukemic and antiviral compound 9-norbornyl-6-chloropurine displaced both passive and facilitated diffusion. 302 Given that radioisotopes may alter molecular permeation and limit structural diversity and throughput analysis, 303 radiolabeling is less common than fluorescence-based techniques for membrane permeation studies.…”

Synthesis of Novel Purine‐Based Coxsackievirus Inhibitors Bearing Polycylic Substituents at the N‐9 Position

“…Despite our continuing efforts the mechanism of action of these compounds is still unknown. Numerous compounds that exerted antiviral activity against CVB3 were also studied for the inhibition of phosphatidylinositol 4‐kinase (PI4K)IIIα and PI4KIIIβ.…”

New antitumor 6-chloropurine nucleosides inducing apoptosis and G2/M cell cycle arrest

“…Voller et al accomplished substitutions at different positions of a 6-aminopurine scaffold and have shown that some of the ribosides exhibited micromolar anticancer activity while their N 7 -or N 9 -linked glucoside analogues were not active [8]. In addition, a 9-norbornyl-6-chloropurine was recently reported as a novel antileukemic compound [10]. The previously reported anticancer potential of 6-chloropurine derived compounds encouraged us to investigate, for the first time, a series of purines embodying a 6-chloro substitution (CP) or both 6-chloro-and 2-acetamido groups (ACP), linked at N 7 or N 9 to perbenzylated D-glucosyl, D-mannosyl and Dgalactosyl residues.…”