The synthesis, characterization, anti-HIV activity and cytotoxicity of dendrimers of (–)-β-D-(2R,4R)-dioxolane-thymine (DOT) and polyethylene glycol (PEG)–DOT conjugates are described. Dendrimers in this study were polyamidoamine (PAMAM) generation 2.0, 3.0, 5.0 and 6.0, along with 8.0-branched PEG with a molecular weight of 40 kDa. DOT was attached to PAMAM dendrimers or branched PEG via ester or phosphate groups. Size exclusion chromatography was used to purify the dendrimers and PEG conjugates, which were characterized by NMR and MALDI—TOF mass spectrometry. The synthesized PAMAM dendrimers and PEG conjugates were evaluated for anti-HIV activity against HIV-1LAI in primary human peripheral blood mononuclear cells (PBMCs) and cytotoxicity in PBMCs, CEM and Vero cells. PAMAM dendrimers of DOT with ester linkages and particularly phosphate linkers showed an increase in anti-HIV potency in comparison with DOT alone (140- and 56-fold, respectively). Unfortunately, the PAMAM dendrimers also exhibited increased cytotoxicity. Anti-HIV activity of PEG—DOT conjugates was found to be lower than that of DOT.
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