cycloSal-pronucleotides of 2 '-fluoro-ara- and 2 '-fluoro-ribo-2 ',3 '-dideoxyadenosine as a strategy to bypass a metabolic blockade

Novel, lipophilic cycloSal triesters 4a-c and 5a-c were synthesized, respec tively, from the ara- and ribo-configurated 2'-fluorinated-2',3'-dideoxyade nosines 2 and 3. The cycloSal phosphotriesters were used as tools to study the effects of the two different sugar pucker conformations induced by two opposite configurations of the fluorine substituent at C2' of the dideoxyri bose moiety. F-ara-ddA (2) is known to be an active anti-HIV agent, whereas the ribo-analogue 3 is inactive. Hydrolysis studies with the triester prec ursors 4a-c and 5a-c showed selective formation of the monophosphates of 2 and 3. The lipophilicity of the triester prodrugs was considerably increase d by the cycloSal mask with respect to ddA (1), F-ara-ddA (2), and F-ribo-d dA (3). Phosphotriesters 4 and 5 proved to be completely resistant to ADA a nd AMPDA deamination. In parallel experiments, ribo-nucleoside 3 showed a 5 0-fold faster deamination rate relative to the ara-analogue 2. Against HIV in CEM cells, the phosphotriesters 4 proved to be 10-fold more potent than the parent nucleoside 2. Furthermore, the prodrugs 4 were active against MS V-induced transformation of C3H/3T3 fibroblasts, while 2 was inactive. More interestingly, the ribo-configurated phosphotriesters 5, prepared from the inactive F-ribo-ddA (3), showed a level of anti-HIV activity that was even higher than that of F-ara-ddA (2). Our findings clearly prove that the app lication of the cycloSal-pronucleotide concept to F-ribo-ddA (3) overcomes a metabolic blockade in the formation of the corresponding monophosphate.