SYNTHESIS AND IN VITRO ANTI-HIV ACTIVITY OF LIPOPHILIC DIDEOXYNUCLEOSIDES

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2-Amino-6-halo-2',3'-dideoxypurine ribofuranosides (6-halo-ddGs) and 6- halo-ddPs (6-halo-ddls) have been shown to suppress the infectivity, replication and cytopathic effect of HIV (Shirasaka et al. Proc. Natl. Acad. Sci. USA. 87:9426-9430, 1990). 2-Amino-6-fluoro-, 2-- amino-6-chloro-, and 6-fluoro-ddPs showed a potent activity against HIV comparable to that of 2',3'-dideoxyinosine (ddl) or 2',3'-dideoxyguanosine (ddG), and completely blocked the infectivity of HIV without affecting the growth of target cells. These compounds have also shown a potent activity against HIV-2 and AZT-resistant HIV-1 variants in vitro. Several of the 6-halogen-containing ddPs have been found to have substantial lipophilic character. The lipophilicity order was: 2-amino-6-iodo is greater than 2-amino-6-bromo is greater than 2-amino-6-chloro is greater than 2-amino-6-fluoro is much greater than ddG is greater than ddI with a log P range from +0.5 to -1.2. All eight 6-halogen-containing ddPs were substrates for adenosine deaminase (ADA). In the presence of an ADA-inhibitor, 2'deoxycoformycin, all 6-halogen-containing ddPs failed to exert their in vitro antiretroviral effects.