SYNTHESIS, IN-VITRO BIOLOGICAL STABILITY, AND ANTI-HIV ACTIVITY OF 6-HALO-6-ALKOXY(OR AZIDO)-5,6-DIHYDRO-3'-AZIDO-3'-DEOXYTHYMIDINE DIASTEREOMERS AS POTENTIAL PRODRUGS TO 3'-AZIDO-3'-DEOXYTHYMIDINE (AZT)

A new class of 5-halo-6-alkoxy(or azido)-5,6-dihydro-3'-azido-3'-deoxythymides was investigated as potential anti-AIDS drugs. These 5,6-dihydro derivatives, which are also potential prodrugs to 3'-azido-3'-deoxythymidine (AZT), were designed in an effort to enhance the duration of action, lipophilicity, and cephalic delivery to the central nervous system. The 5-halo-6-alkoxy(or azido)-5,6-dihydro-3'-azido-3'-deoxythymidines, which differ in configuration at the C-5 and C-6 positions, were synthesized by the regiospecific addition of XR (X = Br, Cl, I; R = alkoxy, azido) to the 5,6-olefinic bond of AZT. The 5-halo-6-methoxy-5,6-dihydro derivatives of AZT are more lipophilic (P = 3.3-18.8 range) than the parent compound AZT (P = 1.29). These 5-halo-6-methoxy-5,6-dihydro compounds, like AZT, did not undergo glycosidic bond cleavage upon incubation with Escherichia coli thymidine phosphorylase. Regeneration of the 5,6-olefinic bond to give AZT, up on incubation of the 5-halo-6-methoxy-5,6-dihydro compounds with glutathione, mouse blood, or mouse liver homogenate, was dependent upon the nature of the 5-halo substituent I > Br). No 5,6-olefinic bond regeneration was observed for the 5-chloro analogs. The ability of these 5-halo-6-alkoxy (or azido)-5,6-dihydro 3'-azido-3'-deoxythymidines to protect CEM cells against HIV-induced cytopathogenicity was evaluated. Structure-activity studies showed that the C-5 substituent (I, Br, Cl) was a determinant of anti-HIV-1 activity where the potency order was I greater than or equal to Br > Cl. In the 5-bromo-series of compounds, the C-6 substituent was also a determinant of activity where 6-OMe and 6-OEt substituents exhibited a greater potency than the corresponding 6-i-PrO, 6-(1-octyloxy), 6-(1-hexadecyloxy), and 6-azido analogs. All of the 5-chloro-6-substituted-5,6-dihydro compounds were inactive, except for the approximately equipotent 6-OMe and 6-azido diastereomeric mixtures which were 2-3 log units less active than the reference drug AZT. The configuration at the C-5 and C-6 positions also influenced potency where the activity of the 5R,6R-diastereomer was generally greater than that of the corresponding 5S,6S-diastereomer. The most potent anti-HIV-1 agents, which included the (5R,6R)-5-bromo-6-methoxy, (5R,6R)-5-iodo-6-methoxy, (5S,6S)-5-iodo-6-methoxy, and (5R,6R)-5-bromo-6-ethoxy analogs of AZT, were equipotent to the reference drug AZT. These 5-iodo(bromo)-6-methoxy-5,6-dihydro derivatives of AZT are potential prodrugs to AZT that provide a rapid release of AZT in vivo.