Synthesis and anti-HIV activity of some novel substituted dialkyl phosphate derivatives of AZT and ddCyd

The reaction of thymidine, AZT (Fig. 1, compound 1) and ddCyd (Fig. 1, compound 2) with bis(2,2,2-tri-chloroethyl) phosphorochloridate gave novel 5'-bis(2,2,2-trichloroethyl) phosphates, characterized by spectroscopic and analytical data. Analogous reactions with bis(2,2,2-trifluoroethyl) phosphorochloridate gave the corresponding AZT and ddCyd derivatives. In both of the ddCyd reactions, by-products were isolated and characterized as O5', N4-diphosphorylated materials. It was hoped that the 5'-phosphate triesters might act as membrane-soluble pro-drugs of the bio-active free nucleotides of AZT or ddCyd. In fact, all of the 5'-phosphate derivatives of AZT and ddCyd displayed anti-HIV activity in vitro. Surprisingly, the thymidine compound also displayed very slight anti-HIV activity. The striking activity of the AZT and ddCyd derivatives is attributed to the metabolic instability of the substituted trialkyl phosphate moiety.