Synthesis and evaluation of 2′-substituted cyclobutyl nucleosides and nucleotides as potential anti-HIV agents

A series of 2′-substituted cyclobutyl nucleoside analogs were efficiently prepared by constructing the core cyclobutyl ring using different [2+2] cycloaddition approaches. The triphosphate derivative of a cyclobutyl nucleoside was also synthesized and evaluated against wild-type and mutant HIV reverse transcriptases (RT). Whereas the nucleoside analogs were inactive against HIV-1 in culture, the nucleotide showed good activity not only against wild-type and recombinant HIV RT (IC50 = 4.7, 6.9 μM), but also against the M184I and M184V mutants (IC50 = 6.1, 6.9 μM) in cell-free assays.

Graphical abstractSeveral 2′-substituted cyclobutyl nucleosides were synthesized and evaluated as anti-HIV agents. Whereas the cyclobutyl nucleosides were not active against HIV in culture, the triphosphate forms were quite active against wild-type and mutant forms of HIV reverse transcriptase (RT).Figure optionsDownload full-size imageDownload as PowerPoint slide