1,3-dioxolanylpurine nucleosides (2R,4R) and (2R,4S) with selective anti-HIV-1 activity in human lymphocytes

Abstract

In order to study the structure-activity relationships of dioxolane nucleosides as potential anti-HIV-1 agents, various enantiomers of pure dioxolanylpurine nucleosides were synthesized and evaluated against HIV-1 in human peripheral blood mononuclear cells. The enantiomerically pure key intermediate 1, which was synthesized in nine steps from 1,6-anhydro-beta-D-mannose, was condensed with 6-chloropurine, 6-chloro-2-fluoropurine, and 2,6-dichloropurine in the presence of TMS triflate. The chloro or fluoro substituents were readily converted into amino, N-methylamino, hydroxy, methoxy, thiol, and methylthio under appropriate reaction conditions. Upon evaluation of these dioxolanes, the guanine derivative 24 exhibited the most potent anti-HIV-1 activity without cytotoxicity up to 100 microM in various cells. The decreasing antiviral activity order of beta-isomers was as follows: guanine > 6-chloro-2-aminopurine > 2-fluoroadenine > or = adenine > or = 2,6-diaminopurine > hypoxanthine > 2-chloroadenine > 6-chloropurine approximately equal to N6-methyladenine approximately equal to 6-mercaptopurine approximately equal to 6-(methylthio)purine.