Synthesis and anti-HIV Activity of Some Novel Substituted Dialkyl Phosphate Derivatives of AZT and ddCyd

Abstract

The reaction of thymidine, AZT (Fig. 1, compound 1) and ddCyd (Fig. 1, compound 2) with bis(2,2,2-trichloroethyl) 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′, W4-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.