NEW LIPOPHILIC ALKYL ACYL DINUCLEOSIDE PHOSPHATES AS DERIVATIVES OF 3'-AZIDO-3'-DEOXYTHYMIDINE - INHIBITION OF HIV-1 REPLICATION IN-VITRO AND ANTIVIRAL ACTIVITY AGAINST RAUSCHER LEUKEMIA-VIRUS INFECTED MICE WITH DELAYED TREATMENT REGIMENS/

The antiretroviral activity of two new lipophilic derivatives of azido thymidine (AZT), -(3'-5')-2',3'-deoxythymidine(N-4-hexadecyldC-AZT) an d 5')-3'-azido-2',3'-deoxythymidine(N-4-palmitoyldC- AZT) was evaluate d in comparison to AZT. Tn vitro the drugs were tested in human immuno deficiency virus 1 (HIV-1) infected CD4(+) HeLa and H9 cells. The in v ivo antiviral effect of these derivatives was analysed in Rauscher leu kemia virus (RLV) infected mice. The derivatives were incorporated int o small liposomes. In vitro both derivatives inhibited virus prolifera tion in both HIV-1 infected cell lines in a similar dose-responsive ma nner as AZT. In a plaque reduction assay, using HeLa cells, the IC50 v alues were 0.035 mu M for AZT, 0.5 mu M for N-4-hexadecyldC-AZT and 4. 5 mu M for N-4-palmitoyldC-AZT, whereas p24 antigen analysis on H9 cel ls gave IC50 values of 0.005 mu M, 0.05 mu M and 0.05 mu M, respective ly. 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, an d 11 and 7 and 11 only. While i.p. treatment with total doses of 380-1 140 mg/kg free AZT resulted in 10-30% inhibition of RLV induced spleno megaly, the derivatives gave inhibitions of 37-94%. Late onset of trea tment with the derivatives was significantly more effective as compare d to free AZT. Intravenous treatment with N-4-hexadecyldC-AZT was effe ctive, but with AZT was inactive. The discrepancy in antiviral activit y of the AZT derivatives found between the in vitro and in vivo test s ystems emphasizes the importance of investigating the activity of drug derivatives in vivo.