STRUCTURE-ACTIVITY-RELATIONSHIPS OF BETA-D-(2S,5R)-1,3-OXATHIOLANYL AND ALPHA-D-(2S,5S)-1,3-OXATHIOLANYL NUCLEOSIDES AS POTENTIAL ANTI-HIV AGENTS

The beta-D-(2S,5R)-and alpha-D-(2S,5S)-1,3-oxathiolanylpyrimidine and -purine nucleosides with natural nucleoside configuration were synthes ized and evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells. The key intermediate 14, which was utilized for the synt hesis of various nucleosides, was synthesized from D-mannose or D-gala ctose. Condensation of the acetate 14 with thymine, uracil, cytosine, and 5-substituted uracils and cytosines gave various pyrimidine nucleo sides. The acetate 14 was also condensed with 6-chloropurine and 6-chl oro-2-fluoropurine which were converted to various purine nucleosides. In the case of thymine, uracil, and 5-substituted uracil derivatives, most of the compounds did not exhibit any significant anti-HIV activi ty except 5-fluorouracil (alpha-isomer) derivative 55. Among 5-substit uted cytosine analogues, 5-bromocytosine derivative (beta-isomer) 68 w as found to be the most potent anti-HIV agent. In the case of purine d erivatives, inosine analogue (beta-isomer) 78 was found to be the most potent anti-HIV agent in the 6-substituted purines and 2-amino-6-chlo ropurine derivative (beta-isomer) 90 showed the most potent activity i n the 2,6-disubstituted purine series. The beta-isomers of 6-chloropur ine (74), adenine (76), and N6-methyladenine (77) derivatives showed s imilar potencies against HIV-1, and the corresponding alpha-isomers al so exhibited significant anti-HIV activity, although they were general ly less potent than the beta-isomers.