RESUMEN
The concise synthesis of 5,6-dihydrovaltrate (2), the bioisostere of valtrate (1) showing anti-HIV activity by inhibition for nuclear export of Rev, has been achieved from the commercially available iridoid genipin (3). Analysis of steric influence of the substituents linked to the three hydroxyl groups was conducted by the synthesized three analogs (2a-2c). Consequently, attenuation of steric hindrance around the epoxy portion was revealed to enhance inhibitory potency for Rev-export. In addition to this finding, 1-acetoxy analog 2b was disclosed as the promising Rev-export inhibitor superior to 1.
Asunto(s)
Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Iridoides/química , Iridoides/farmacología , Productos del Gen rev del Virus de la Inmunodeficiencia Humana/metabolismo , Fármacos Anti-VIH/síntesis química , Núcleo Celular/metabolismo , Infecciones por VIH/metabolismo , VIH-1/metabolismo , Células HeLa , Humanos , Glicósidos Iridoides/síntesis química , Glicósidos Iridoides/química , Iridoides/síntesis química , Transporte de Proteínas/efectos de los fármacosRESUMEN
Exploration for inhibitors against expression of IgE receptor (Fc epsilonRI) on human mast cell, a significant trigger to acute and chronic allergic symptoms, disclosed epigallocatechin gallate (EGCG), epicatechin gallate, and gallocatechin gallate as active principles. Additionally, the anthocyanidin, delphinidin, and the flavone, tricetinidin, possessing a pyrogallol function were also revealed to suppress expression of Fc epsilonRI. Structure-activity relationship analysis among catechins, anthocyanidins, and flavones revealed the pyrogallol moiety to be crucial for biological potency. Furthermore, EGCG was clarified to reduce generation of gamma-chain subunit to suppress expression of Fc epsilonRI on human mast cells.
Asunto(s)
Antocianinas/farmacología , Antialérgicos/farmacología , Catequina/farmacología , Flavonoides/farmacología , Expresión Génica/efectos de los fármacos , Mastocitos/efectos de los fármacos , Receptores de IgE/genética , Antocianinas/química , Antialérgicos/química , Catequina/análogos & derivados , Catequina/química , Línea Celular , Flavonas , Flavonoides/química , Humanos , Hipersensibilidad/tratamiento farmacológico , Mastocitos/metabolismo , Receptores de IgE/metabolismoRESUMEN
Rational design by the MO calculation disclosed 5,6-dihydrovaltrate (2) as the bioisostere of valtrate (1), the Rev-export inhibitor with anti-HIV activity. The synthesis of 2 was accomplished by ingenious use of asymmetric Diels-Alder reaction and stereoselective epoxidation associated with the adjacent hydroxyl group. Because of similar biological potency to 1, the analog 2 should be recognized as a promising scaffold for new anti-HIV agents with an unprecedented mechanism of action, inhibition for nuclear export of Rev protein, in the conventional remedy.