Synthesis of Some Novel Dialkyl Phosphate Derivatives of 3′-Modified Nucleosides as Potential Anti-AIDS Drugs

Abstract

The reaction of thymidine with diethyl, dipropyl, and dibutyl phosphorochloridates yields novel 5′-(dialkyl phosphates), characterized by spectroscopic and analytical data. These are readily mesylated at the 3′-position. Similar reaction of 3′-O-acetyl and 3′-O-ethyl thymidine with dialkyl phosphorochloridates gives an analogous series of compounds. Lastly, reaction of the anti-AIDS drug AZT with these phosphorylating agents gives the corresponding 3′-azido products. It was hoped that these might act as membrane-soluble pro-drugs of the bio-active free nucleotides of AZT and that the alternative 3′-substituents might also confer similar activity. In fact, none of the compounds studied displayed any anti-HIV activity in vitro. This is attributed to the metabolic stability of the trialkyl phosphate moiety.