RESUMEN
Herein, we describe our studies on the synthesis of 1α,25-dihydroxyvitamin D3 analogs possessing a benzene ring replacing the natural 5-membered D-ring by the Wittig-Horner and dienyne approaches. A key feature is the synthesis of a Cr(CO)3-complexed previtamin D derivative that enables the construction of vitamin D analogs with aromatic D-ring through a thermal [1,7]-H sigmatropic shift. This study establishes the basis for the design of new vitamin D analogs containing aromatic D-ring, complexed or uncomplexed to Cr(CO)3 type moieties for specific molecular recognition and drug research and development.
Asunto(s)
Técnicas de Química Sintética/métodos , Diseño de Fármacos , Vitamina D/síntesis química , Relación Estructura-ActividadRESUMEN
An improved synthetic route to 1α,25-dihydroxyvitamin D(3) des-side chain analogues 2 a and 2 b with substituents at C18 is reported, along with their biological activity. These analogues display significant antiproliferative effects toward MCF-7 breast cancer cells and prodifferentiation activity toward SW480-ADH colon cancer cells; they are also characterized by a greatly decreased calcemic profile. The crystal structure of the human vitaminâ D receptor (hVDR) complexed to one of these analogues, 20(17â18)-abeo-1α,25-dihydroxy-22-homo-21-norvitamin D(3) (2 a) reveals that the side chain introduced at position C18 adopts the same orientation in the ligand binding pocket as the side chain of 1α,25-dihydroxyvitamin D(3).
Asunto(s)
Calcitriol/química , Animales , Sitios de Unión , Calcitriol/síntesis química , Calcitriol/farmacología , Línea Celular Tumoral , Simulación por Computador , Humanos , Receptores de Calcitriol/química , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , PorcinosRESUMEN
A review of the design and synthesis of structural analogs of the vitamin D hormone recently investigated in our laboratories, and the first report on a new class of vitamin D analogs characterized by an aromatic D-ring, is described.