Syntheses of 4 '-C-ethynyl-beta-D-arabino- and 4'-C-ethynyl-2'-deoxy-beta-D-ribo-pentofuranosylpyrimidines and -purines and evaluation of their anti-HIV activity

4'-C-Ethynyl-beta -D-arabino- and 4'-C-ethynyl-2'-deoxy-beta -D-ribo-pentof uranosylpyrine and -purine nucleosides were synthesized and evaluated for t heir in vitro anti-HIV activity. The key intermediate, 4-C-ethynyl- or 4-C- triethylsilylethynyl-D-ribo-pentofuranose, was prepared from D-glucose and glycosidated with various pyrimidine or purine bases. The arabino pyrimidin e derivatives were prepared from the corresponding ribo derivatives via O-2 ,2'-anhydro nucleosides. The 2'-deoxy-ribo derivatives were synthesized by radical reduction of 2'-bromo or 2'- phenoxythiocarbonyloxy nucleosides. Am ong these 4'-C-ethynyl nucleosides, seven analogues proved to be potent aga inst HIV-1 in vitro with EC50 values ranging from 0.0003 to 0.03 muM. These compounds also exerted activity against clinical and multi-dideoxy-nucleos ide-resistant HIV-1 strains with comparable EC50 values. Three such 4'-C-et hynyl-2'-deoxypurine analogues including 4'-C-ethynyl-2'-deoxyadenosine and 4'-C-ethynyl-2,6-diamino-2'-deoxy-purine were less cytotoxic [selectivity indices (SIs): 975-2733] than three 4'-C-ethynyl-2-deoxycytidine analogues (SIs: 63-363). 4'-C-Ethynyl-5-fluoro-2'-deoxycytidine was least toxic (SI: >3333) and potent against all HIV strains tested.