Four 2-amino-6-halo- and four 6-halo-2',3'-dideoxypurine ribofuranosides (ddP) were synthesized and tested for in vitro activity to suppress the infectivity, cytopathic effect, gag protein expression, and DNA synthesis of HIV. The comparative order of in vitro anti-HIV activity of the eight 6-halo-ddPs was : 2-amino-6-fluoro, 2-amino-6-chloro, 6-fluoro > 2-amino- 6-bromo > 2-amino-6-iodo, 6-chloro > 6-bromo > 6-iodo. 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 (ddI) or 2',3'-dideoxyguanosine- (ddG), and completely blocked the infectivity of HIV without affecting the growth of target cells. The lipophilicity order was : 2-amino-6-iodo > 2- amino-6-bromo > 2-amino-6-chloro > 2-amino-6-fluoro >> ddG > ddl. All eight 6-halo-ddPs were substrates for adenosine deaminase (ADA). The relative rate of hydrolysis by ADA was : ddA, 2-amino-6-fluoro >> 2-amino-6-chloro, 2-amino-6-bromo > 2-amino-6-iodo. In the presence of an ADA-inhibitor, 2'-deoxycoformycin, all 2-amino-6-halo- and 6-halo-ddPs failed to exert their in vitro antiretroviral effect. Taken together, these compounds may represent a new class of lipophilic prodrugs for ddl and ddG, and may also provide a new strategy for endowing therapeutic purine nucleosides with desirable lipophilicity.
