Biochemical pharmacology of 2 '-fluoro-2 ',3 '-dideoxyarabinosyladenine, an inhibitor of HIV with improved metabolic and chemical stability over 2 ',3 '-dideoxyadenosine

We have investigated some properties of the acid stable, 2'-arafluoro-substituted congeners of dideoxyadenosine (ddA) and dideoxylnosine (ddl) in order to understand their potential for in vivo utility as anti-HIV agents. Activities of 2'-fluoro-2',3'-dideoxyarabinosyl-adenine (FddA) and hypoxanthine (Fddl) against human immunodeficiency virus (HIV) in cells are similar and are about an order of magnitude lower than those of ddA and ddl. FddA is a much poorer substrate than ddA for adenosine deaminase, and is deaminated about 50-fold slower at pharmacological concentrations. The product Fddl is (in contrast to ddl) resistant to cleavage by purine nucleoside phosphorylase. As for ddl, Fddl is phosphorylated by a 5'-nucleotidase, using inosine monophosphate (IMP) as the phosphate donor. In cells, both FddA and Fddl are phosphorylated to the triphosphate of FddA (FddATP). However, the concentration of FddATP produced from FddA is about two-to five-fold higher than from Fddl. FddATP is extremely stable in cells and persists with a half-life of 20h after removal of FddA from the medium. Using HIV reverse transcriptase, FddATP is a less efficient inhibitor than ddATP by about 20-fold. Thus the activity of these compounds against HIV in cells correlates well with the intracellular concentration and potency of their triphosphates. If the efficacy of ddl in clinical trials is the result of its activity in certain cell types, the fluoro congeners could be active in similar cells since they use the same enzymes for activation to the active triphosphorylated forms. The reduction in potency may, to some extent, be offset by the greater stability to acid and enzyme degradation. Thus further evaluation of FddA and Fddl as anti-HIV agents is warranted.