Synthesis of some novel dialkyl phosphate derivatives of 3 '-modified nucleosides as potential anti-AIDS drugs

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.