Strong and selective inhibitors of HBV-replication between novel N4-hydroxy-and 5-methyl-beta-L-deoxycytidine analogues

Item Type:	Article
Title:	Strong and selective inhibitors of HBV-replication between novel N4-hydroxy-and 5-methyl-beta-L-deoxycytidine analogues
Creators Name:	Matthes, E. and Funk, A. and Krahn, I. and Gaertner, K. and von Janta-Lipinski, M. and Lin, L. and Will, H. and Sirma, H.
Abstract:	Novel N(4)-hydroxy- and 5-methyl-modified beta-L-deoxycytidine analogues were synthesized and evaluated as anti-hepatitis B virus (HBV) agents. Their in vitro efficiency was investigated in stably HBV-transfected HepG2.2.15 cells. beta-L-2,3-Didehydro-2,3-dideoxy-N(4)-hydroxycytidine (beta-L-Hyd4C) was most effective in reducing secreted HBV DNA (EC50=0.03 microM) followed by beta-L-2,3-dideoxy-3-thia-N(4)-hydroxycytidine (EC50=0.51 microM), beta-L-2,3-dideoxy-N(4)-hydroxycytidine (EC50=0.55 microM), and beta-L-5-methyl-2-deoxycytidine (EC50=0.9 microM). The inhibition of the presumed target, the HBV DNA polymerase, by the triphosphates of some of the beta-L-cytidine derivatives was also assessed. In accordance with the cell culture data, beta-L-Hyd4C triphosphate was the most active inhibitor with an IC50 value of 0.21 microM. The cytotoxicity of some of the 4-NHOH-modified beta-L-nucleosides was dramatically reduced in comparison to the corresponding cytidine analogues with the unmodified 4-NH2-group. The CC50-values for beta-L-Hyd4C in HepG2 and HL-60 cells were 2,500 microM and 3,500 microM, respectively. In summary, our results demonstrate that at least beta-L-Hyd4C recommends as highly efficient and extremely selective inhibitor of HBV replication for further investigations.
Keywords:	Antiviral Agents, Hepatocellular Carcinoma, Tumor Cell Line, DNA-Directed DNA Polymerase, Deoxycytidine, Drug Dose-Response Relationship, HL-60 Cells, Hepatitis B Virus, Inhibitory Concentration 50, Liver Neoplasms, Molecular Structure, Time Factors, Transfection, Virus Replication
Source:	Antimicrobial Agents and Chemotherapy
ISSN:	0066-4804
Publisher:	American Society for Microbiology
Volume:	51
Number:	7
Page Range:	2523-2530
Date:	July 2007
Official Publication:	https://doi.org/10.1128/AAC.00001-07
PubMed:	View item in PubMed

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