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 (IC(50)=4.7, 6.9 microM), but also against the M184I and M184V mutants (IC(50)=6.1, 6.9 microM) in cell-free assays.
Li
Yongfeng
Y
Department of Chemistry, Emory University, Atlanta, GA 30322, USA.
Mao
Shuli
S
Hager
Michael W
MW
Becnel
Kimberlynne D
KD
Schinazi
Raymond F
RF
Liotta
Dennis C
DC
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D002478:Cells, Cultured; D003503:Cyclobutanes / Q000737:chemistry* / Q000494:pharmacology; D024882:Drug Resistance, Viral; D006801:Humans; D008956:Models, Chemical; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D009711:Nucleotides / Q000737:chemistry / Q000494:pharmacology*; D017354:Point Mutation; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D003503:Cyclobutanes; D009705:Nucleosides; D009711:Nucleotides; D018894:Reverse Transcriptase Inhibitors