L-beta-(2S,4S)- and L-alpha-(2S,4R)-dioxolanyl nucleosides as potential anti-HIV agents: asymmetric synthesis and structure-activity relationships.

Abstract

In order to study the structure-activity relationships of L-(2S,4S)- and L-(2S,4R)-dioxolanyl nucleoside as potential anti-HIV agents, various enantiomerically pure L-(2S,4S)- and (2S,4R)-dioxolanylpyrimidine and -purine nucleosides have been synthesized and evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells. The enantiomerically pure key intermediate 8 has been synthesized in six steps from 1,6-anhydro-beta-L-gulose (2), and compound 8 was condensed with 5-substituted pyrimidines, 6-chloropurine, and 2,6-disubstituted purine to obtain various dioxolanylpyrimidine and -purine nucleosides, respectively. Among the compound synthesized, 5-fluorocytosine derivative 29 was found to exhibit the most potent anti-HIV activity (EC50 = 0.0012 microM) although it was toxic (IC50 = 10.0 microM). The order of anti-HIV potency of pyrimidine analogues was as follows: 5-fluorocytosine (beta-isomer) > cytosine (beta-isomer) > 5-fluorocytosine (alpha-isomer) > 5-iodocytosine (beta-isomer) > cytosine (alpha-isomer) > 5-bromocytosine (beta-isomer) > thymine (beta-isomer) > 5-methylcytosine (alpha-isomer) > 5-iodocytosine (alpha-isomer) > 5-chlorocytosine (beta-isomer). The anti-HIV potency of purine analogues was found to be in the following decreasing order: 2,6-diaminopurine (beta-isomer) > 2-chloroadenine (alpha-isomer) > 2-fluoroadenine (beta-isomer) > adenine (beta-isomer) > 2-amino-6-chloropurine (alpha-isomer) > 2-amino-6-chloropurine (beta-isomer) > guanine (beta-isomer) > 2-fluoroadenine (alpha-isomer) > adenine (alpha-isomer) > 2,6-diaminopurine (alpha-isomer) > N6-methyladenine (beta-isomer). It is interesting to note that the alpha-5-fluorocytosine analogue exhibited an excellent anti-HIV activity (EC50 = 0.063 microM) without cytotoxicity up to 100 microM in PBM cell.