cycloSal-pronucleotides of 2 ',3 '-dideoxyadenosine and 2 ',3 '-dideoxy-2 ',3 '-didehydroadenosine: Synthesis and antiviral evaluation of a highly efficient nucleotide delivery system

The synthesis, hydrolysis, and antiviral evaluation of novel, lipophilic cy cloSal-ddAMP (9a-d) and cycloSal-d4AMP (10a-d) derivatives of the antiviral purine dideoxynucleoside analogues 2',3'-dideoxyadenosine (ddA) (2) and 2' ,3'-dideoxy-2',3'-didehydroadenosine (d4A) (3) are reported. These potentia l pronucleotides release ddAMP (7) or d4AMP (8) selectively by a controlled , chemically induced tandem reaction. All new compounds 9 and 10a-d were sy nthesized in good yields using our previously reported phosphorus(III) meth od starting from substituted salicyl alcohols 14a-h. The phosphotriesters 9 and 10 were obtained with a stereochemical preference of 2:1 with respect to the configuration at the phosphorus center. In an 1-octanol/water mixtur e phosphotriesters 9 and 10 exhibited 7-43-fold higher lipophilicity than t he parent nucleosides ddA (2) and d4A (3) as judged by their log P values. In hydrolysis studies, 9 and 10 decomposed under mild aqueous basic conditi ons releasing solely ddAMP (7) and d4AMP (8), as well as the diols 14. Furt her hydrolysis studies under acidic conditions showed a marked increase in stability with respect to the acid-catalyzed cleavage of the glycosyl bond. Phosphotriesters 9 and 10 exhibited antiviral potencies against wild-type HIV-1 and HIV-2 strains in human T-lymphocyte (CEM/O) cells that were, resp ectively, 100- and 600-fold higher than those of ddA (2) and d4A (3). Furth ermore, all triesters 9 and 10 were markedly more active than the correspon ding ddI compounds 11 and 12, which supports the concept of the delivery of the adenine nucleotides. Studies with adenosine deaminase (ADA) and adenos ine monophosphate deaminase (AMPDA) showed that the triesters were not subs trates for enzymatic deamination. The studies reported herein demonstrate c onclusively that the cycloSal triesters deliver exclusively the nucleotides ddAMP and d4AMP, not only under chemical-simulated hydrolysis but also und er intracellular conditions fulfilling the adenosine deaminase bypass premi se.