RESUMEN
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.
Asunto(s)
Alpinia/química , Fármacos Anti-VIH/farmacología , Alcoholes Bencílicos/farmacología , Genes rev/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Animales , Fármacos Anti-VIH/química , Alcoholes Bencílicos/química , Bovinos , VIH-1/efectos de los fármacos , Células HeLa , Humanos , Hidrocarburos Halogenados/química , Hidrocarburos Halogenados/farmacología , Extractos Vegetales/química , Extractos Vegetales/farmacologíaRESUMEN
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.