5'-O-PHOSPHONOMETHYL-2',3'-DIDEOXYNUCLEOSIDES - SYNTHESIS AND ANTI-HIV ACTIVITY

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-phosphonomethylated derivative 12, which was converted to both the 2',3’-dideoxyuridine analogue 27 and the 2',3’-dideoxycytidine counterpart 29. The 5’-0-phosphonomethyl derivatives of 3’-deoxythymidine (23), 2′,3′-dideoxyuridine (27), 2',3’-dideoxycytidine (29), 3^0-methylthymidine (26), and 3'-amino-3’-deoxythymidine (28) did not show an appreciable anti-HIV activity in MT-4 cells. In contrast, the 5’-0-phosphonomethyl derivatives of 3′-deoxy-3′-fluorothymidine (24) and 3′-azido-3′-deoxythymidine (25) inhibited HIV-1 cytopathogenicity by 50% at a concentration of approximately 1 µm. © 1990, American Chemical Society. All rights reserved.