Journal of Medicinal Chemistry 1993-09-03

Structure-activity relationships of beta-D-(2S,5R)- and alpha-D-(2S,5S)-1,3-oxathiolanyl nucleosides as potential anti-HIV agents.

L S Jeong, R F Schinazi, J W Beach, H O Kim, K Shanmuganathan, S Nampalli, M W Chun, W K Chung, B G Choi, C K Chu

Index: J. Med. Chem. 36(18) , 2627-38, (1993)

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Abstract

The beta-D-(2S,5R)- and alpha-D-(2S,5S)-1,3-oxathiolanylpyrimidine and -purine nucleosides with natural nucleoside configuration were synthesized and evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells. The key intermediate 14, which was utilized for the synthesis of various nucleosides, was synthesized from D-mannose or D-galactose. Condensation of the acetate 14 with thymine, uracil, cytosine, and 5-substituted uracils and cytosines gave various pyrimidine nucleosides. The acetate 14 was also condensed with 6-chloropurine and 6-chloro-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 activity except 5-fluorouracil (alpha-isomer) derivative 55. Among 5-substituted cytosine analogues, 5-bromocytosine derivative (beta-isomer) 68 was found to be the most potent anti-HIV agent. In the case of purine derivatives, inosine analogue (beta-isomer) 78 was found to be the most potent anti-HIV agent in the 6-substituted purines and 2-amino-6-chloropurine derivative (beta-isomer) 90 showed the most potent activity in the 2,6-disubstituted purine series. The beta-isomers of 6-chloropurine (74), adenine (76), and N6-methyladenine (77) derivatives showed similar potencies against HIV-1, and the corresponding alpha-isomers also exhibited significant anti-HIV activity, although they were generally less potent than the beta-isomers.