5′-O-Aliphatic and amino acid ester prodrugs of (−)-β-d-(2R,4R)-dioxolane-thymine (DOT): Synthesis, anti-HIV activity, cytotoxicity and stability studies

A series of (−)-β-d-(2R,4R)-dioxolane-thymine-5′-O-aliphatic acid esters as well as amino acid esters were synthesized as prodrugs of (−)-β-d-(2R,4R)-dioxolane-thymine (DOT). The compounds were evaluated for anti-HIV activity against HIV-1LAI in human peripheral blood mononuclear (PBM) cells as well as for their cytotoxicity in PBM, CEM and Vero cells. Improved anti-HIV potency in vitro was observed for the compound 2–4 (5′-O-aliphatic acid esters) without increase in cytotoxicity in comparison to the parent drug. Chemical and enzymatic hydrolysis of the prodrugs was also studied, in which the prodrugs exhibited good chemical stability with the half-lives from 3 h to 54 h at pH 2.0 and 7.4 phosphate buffer. However, the prodrugs were relatively labile to porcine esterase with the half-lives from 12.3 to 48.0 min.

Figure optionsDownload as PowerPoint slide