Aim: 6-Chloropurines substituted at position 9 with bicyclic skeletons represent promising chemotherapeutic agents. We explored the metabolism and membrane transport of 9-norbornyl-6-chloropurine (NCP) aiming to understand its mechanism of action.
Materials And Methods: The metabolism of NCP was studied in vitro in whole cells (CCRF-CEM), cellular extracts, subcellular fractions and purified enzymes. Transport experiments were conducted in Caco-2 cell monolayers.
Results: Three metabolites were identified, a glutathione conjugate (NCP-GS), NCP-cysteinylglycine and NCP-cysteine. Both glutathione-S-transferase inhibition and glutathione (GSH) depletion prevented metabolite formation and increased the cytotoxicity of NCP. Transepithelial transport (Caco-2) indicated good permeability, with Papp (12.6±0.3) ×10(-5) cm/s. Importantly, the drug induced glutathione depletion in treated cells and affected the activity of several GSH-dependent enzymes.
Conclusion: The novel nucleoside analog NCP represents a promising orally available antileukemic agent, acting through lowering of GSH levels in tumor cells.
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J Enzyme Inhib Med Chem
February 2015
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic , Prague , Czech Republic.
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.
View Article and Find Full Text PDFAnticancer Res
August 2013
Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
Aim: 6-Chloropurines substituted at position 9 with bicyclic skeletons represent promising chemotherapeutic agents. We explored the metabolism and membrane transport of 9-norbornyl-6-chloropurine (NCP) aiming to understand its mechanism of action.
Materials And Methods: The metabolism of NCP was studied in vitro in whole cells (CCRF-CEM), cellular extracts, subcellular fractions and purified enzymes.
Bioorg Med Chem Lett
March 2012
Gilead Sciences & IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic.
We report on the synthesis and the study of the structure-activity relationship of novel 9-norbornyl-6-chloropurine derivatives, which exert selective antiviral activity on the replication of Coxsackievirus B3. In particular, the synthetic approaches towards norbornyl derivatives bearing diverse side chains were studied. The main goal of the study was to determine the influence of the norbornane moiety substitution at positions 5' and 6' on selective antiviral activity with special regard to the liphophilicity profile of the substituent.
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