Abstract
The antiretroviral activity of two new lipophilic derivatives of azidothymidine (AZT), N 4-hexadecyl-2′-deoxyribocytidylyl-(3′-5′)-3′-azido-2′,3′-deoxythymidine( N 4-hexadecyldC-AZT) and N 4-palmitoyl-2′-deoxyribocytidylyl-(3′-5′)-3′-azido-2′,3′-deoxythymidine( N 4-palmitoyldC-AZT) was evaluated in comparison to AZT. In vitro the drugs were tested in human immunodeficiency virus 1 (HIV-1) infected CD4 + HeLa and H9 cells. The in vivo antiviral effect of these derivatives was analysed in Rauscher leukemia virus (RLV) infected mice. The derivatives were incorporated into small liposomes. In vitro both derivatives inhibited virus proliferation in both HIV-1 infected cell lines in a similar dose-responsive manner as AZT. In a plaque reduction assay, using HeLa cells, the IC 50 values were 0.035 μM for AZT, 0.5 μM for N 4-hexadecyldC-AZT and 4.5 μM for N 4-palmitoyldC-AZT, whereas p24 antigen analysis on H9 cells gave IC 50 values of 0.005 μM, 0.05 μM and 0.05 μM, respectively. RLV infected mice were treated with intermittent schedules i.p. or i.v. on days 1, 6, 11, and days 16 or 0, 3, 7, and 11 after infection. Regimens with further delayed drug application were on days 3, 7, and 11 and 7 and 11 only. While i.p. treatment with total doses of 380–1140 mg/kg free AZT resulted in 10–30% inhibition of RLV induced splenomegaly, the derivatives gave inhibitions of 37–94%. Late onset of treatment with the derivatives was significantly more effective as compared to free AZT. Intravenous treatment with N 4-hexadecyldC-AZT was effective, but with AZT was inactive. The discrepancy in antiviral activity of the AZT derivatives found between the in vitro and in vivo test systems emphasizes the importance of investigating the activity of drug derivatives in vivo.
Published Version
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