New 3 '-azido-3 '-deoxythymidin-5 '-yl O-(omega-hydroxyalkyl) carbonate prodrugs: Synthesis and anti-HIV evaluation

Prodrugs of zidovudine (AZT) have been synthesized in an effort to enhance its uptake by HIV-1 infected cells and its anti-HIV activity. The 5'-OH fun ction of AZT was functionalized with various enzymatically labile alkyl gro ups using specific procedures. The prodrug moieties included 5'-O-carbonate , 5'-O-carbamate, and 5'-O-ester. Analogues of the 3'-azido-3'-deoxy-thymid in-5'-yl O-(omega -hydroxyalkyl) carbonate series were particularly interes ting since they were rearranged through an intramolecular cyclic process du ring their enzymatic hydrolysis. Evidence of this prodrug rearrangement was confirmed by comparison of the serum half-lives of 5'-O-carbonate prodrugs with their corresponding 5'-O-ester- and 5'-O-carbamate-AZT prodrugs. Inte restingly, the anti-HIV-1 activities (EC50) of 3'-azido-3'-deoxythymidin-5' -yl O-(4-hydroxybutyl) carbonate 10 in acutely infected MT-4 cells and in p eripheral blood mononuclear cells (PBMCs) were 0.5 nM and 0.78 nM, respecti vely. Compound 10 was 30 to 50 times more potent than its parent drug AZT. Our results suggest that the specific intramolecular rearrangement associat ed with the 3'-azido-3'-deoxythymidin-5'-yl O-(omega -hydroxyalkyl) carbona te prodrugs could explain the remarkable anti-HIV-1 activity of this series of AZT prodrugs. Prodrug 10 may therefore have better clinical potential t han AZT for the treatment of AIDS.