Open AccessStrong and Selective Inhibitors of Hepatitis B Virus Replication among Novel N 4 -Hydroxy- and 5-Methyl-β- l -Deoxycytidine Analogues
Author(s) -
E. Matthes,
Anneke Funk,
Inge Krahn,
K. Gaertner,
Martin von JantaLipinski,
Li Lin,
Hans Will,
Hüseyin Sirma
Publication year - 2007
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.00001-07
Subject(s) - cytidine , deoxycytidine , hepatitis b virus , microbiology and biotechnology , chemistry , in vitro , cell culture , dna synthesis , stereochemistry , virology , virus , biology , biochemistry , enzyme , gemcitabine , chemotherapy , genetics
Novel N4 -hydroxy- and 5-methyl-modified β-l -deoxycytidine analogues were synthesized and evaluated as anti-hepatitis B virus (HBV) agents. Their in vitro efficiencies were investigated in HepG2.2.15 cells stably transfected with HBV. β-l -2′,3′-Didehydro-2′,3′-dideoxy-N4 -hydroxycytidine (β-l -Hyd4C) was most effective in reducing secreted HBV DNA (50% effective concentration [EC50 ], 0.03 μM), followed by β-l -2′,3′-dideoxy-3′-thia-N4 -hydroxycytidine (EC50 , 0.51 μM), β-l -2′,3′-dideoxy-N4 -hydroxycytidine (EC50 , 0.55 μM), and β-l -5-methyl-2′-deoxycytidine (EC50 , 0.9 μM). The inhibition of the presumed target, the HBV DNA polymerase, by the triphosphates of some of the β-l -cytidine derivatives was also assessed. In accordance with the cell culture data, β-l -Hyd4C triphosphate was the most active inhibitor, with a 50% inhibitory concentration of 0.21 μM. The cytotoxicities of some of the 4-NHOH-modified β-l -nucleosides were dramatically lower than those of the corresponding cytidine analogues with the unmodified 4-NH2 group. The 50% cytotoxic concentrations for β-l -Hyd4C in HepG2 and HL-60 cells were 2,500 μM and 3,500 μM, respectively. In summary, our results demonstrate that at least β-l -Hyd4C can be recommended as a highly efficient and extremely selective inhibitor of HBV replication for further investigations.