5'-O-Phosphonomethyl-2',3'-dideoxynucleosides: Synthesis and Anti-HIV activity

Article abstract of DOI:10.1021/jm00171a023

5'-O-Phosphonomethylation of different pyrimidine 2',3'-dideoxynucleosides was accomplished by reaction of the latter with diethyl <(p-tolylsulfonyl)oxy>methanephosphonate (1) in the presence of sodium hydride.The base-phosphonomethylated (15-19) and sugar-phosphonomethylated (8-12) derivatives could be readily distinguished by 1H and 13C NMR and MS analysis.Protection of the uracil or thymine residue with a N³-benzoyl group failed to prevent base modification.However, O⁴-methyl-protected 2',3'-dideoxyuridine readily afforded the 5'-O-phosphonomethylatedderivative 12, which was converted to both the 2',3'-dideoxyuridine analogue 27 and the 2',3'-dideoxycytidine counterpart 29.The 5'-O-phosphonomethyl derivatives of 3'-deoxythymidine (23), 2',3'-dideoxyuridine (27), 2',3'-dideoxycytidine (29), 3'-O-methylthymidine (26), and 3'-amino-3'-deoxythymidine (28) did not show an appreciable anti-HIV activity in MT-4 cells.In contrast, the 5'-O-phosphonomethyl derivatives of 3'-deoxy-3'-fluorothymidine (24) and 3'-azido-3'-deoxythymidine (25) inhibited HIV-1 cytopathogenicity by 50percent at a concentration of approximately 1 μM.