RESUMEN
A series of ligands with varying heterocyclic cores and substituents that display a range of selectivity's (up to >100x) for ER-beta over ER-alpha are reported.
Asunto(s)
Receptor beta de Estrógeno/metabolismo , Compuestos Heterocíclicos/farmacocinética , Línea Celular Tumoral , Cristalografía por Rayos X , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/química , Compuestos Heterocíclicos/síntesis química , Humanos , Indicadores y Reactivos , Cinética , Ligandos , Moduladores Selectivos de los Receptores de Estrógeno/química , Relación Estructura-ActividadRESUMEN
A total synthesis of FK-506 (1) is presented. The synthesis features a highly convergent approach utilizing a block coupling strategy. Top and bottom half sections of the molecule are coupled by addition of a vinyl cuprate with a spiroenone. The alpha-allyl aldol functionality is revealed by a reductive opening of the spiroenone system. The labile alpha,beta-diketoamide hemiketal portion of the molecule is prepared by a late stage generation and oxidation of a masked enediol. Top and bottom half segments are themselves derived by coupling of smaller subunits, resulting in a very convergent route.
