RESUMO
In the course of search for the robust analogs of 1'-acetoxychavicol acetate (ACA, 1), the Rev-export inhibitor from the medicinal plant Alpinia galanga, we clarified formation of the quinone methide intermediate ii to be essential for exerting the inhibitory activity of 1. Based on this mechanism of action, the rational design from the MO calculation of the conclusive activation energy to ii resulted in the four halogenated analogs with more potent activity than ACA (1). In particular, the difluoroanalog 20d exhibited approximately four-fold potent activity as compared with 1.
Assuntos
Alpinia/química , Fármacos Anti-HIV/farmacologia , Álcoois Benzílicos/farmacologia , Genes rev/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Animais , Fármacos Anti-HIV/química , Álcoois Benzílicos/química , Bovinos , HIV-1/efeitos dos fármacos , Células HeLa , Humanos , Hidrocarbonetos Halogenados/química , Hidrocarbonetos Halogenados/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologiaRESUMO
Bioassay-guided separation from the MeOH extract of the South American medicinal plant Sida cordifolia resulted in isolation of (10E,12Z)-9-hydroxyoctadeca-10,12-dienoic acid (1) as an unprecedented NES non-antagonistic inhibitor for nuclear export of Rev. This mechanism of action was established by competitive experiment by the biotinylated probe derived from leptomycin B, the known NES antagonistic inhibitor. Additionally, structure-activity relationship analysis by use of the synthesized analogs clarified cooperation of several functionalities in the Rev-export inhibitory activity of 1.
Assuntos
Produtos do Gene rev/metabolismo , Malvaceae/metabolismo , Sinais de Exportação Nuclear , Extratos Vegetais/farmacologia , Transporte Proteico/efeitos dos fármacos , Cromatografia Líquida de Alta PressãoRESUMO
Bioassay-guided separation by use of the fission yeast expressing NES of Rev, an HIV-1 viral regulatory protein, disclosed 1'-acetoxychavicol acetate (ACA, 1) as a new inhibitor for nuclear export of Rev from the roots of Alpinia galanga. Both analysis for mechanism of action with biotinylated probe (2) and several synthesized analogs established crucial portions in 1 for Rev-export inhibitory activity.
