RESUMEN
A novel class of phosphonate derivatives was designed to mimic the interaction of product-like carboxylate based inhibitors of HCV NS3 protease. A phosphonic acid (compound 2) was demonstrated to be a potent HCV NS3 protease inhibitor, and a potential candidate for treating HCV infection. The syntheses and preliminary biological evaluation of this phosphonate class of inhibitor are described.
Asunto(s)
Antivirales/síntesis química , Hepacivirus/efectos de los fármacos , Organofosfonatos/síntesis química , Inhibidores de Serina Proteinasa/síntesis química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/química , Antivirales/farmacocinética , Línea Celular Tumoral , Simulación por Computador , Perros , Descubrimiento de Drogas , Humanos , Organofosfonatos/química , Organofosfonatos/farmacocinética , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacocinética , Proteínas no Estructurales Virales/metabolismoRESUMEN
A highly convergent, enantioselective total synthesis of the potent antitumor agent apoptolidin A has been completed. The key transformations include highly selective glycosylations to attach the C27 disaccharide and the C9 6'-deoxy-l-glucose, a cross-metathesis to incorporate the C1-C10 trienoate unit, and a Yamaguchi macrolactonization to complete the macrocycle. Twelve stereocenters in the polypropionate segments and sugar units were established through diastereoselective chlorotitanium enolate aldol reactions.
Asunto(s)
Antineoplásicos/síntesis química , Glucosa/análogos & derivados , Glucosa/síntesis química , Macrólidos/síntesis química , Pironas/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Glucosa/química , Glicosilación , Macrólidos/química , Macrólidos/farmacología , Estructura Molecular , Pironas/química , Pironas/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
An efficient, enantioselective synthesis of apoptolidinone has been completed, demonstrating the versatility of thiazolidinethione auxiliaries. Three propionate aldol additions and two asymmetric glycolate alkylations function to establish 8 of the 12 stereogenic carbon centers. A cross-metathesis reaction is utilized to assemble the C1-C10 trieneoate fragment and the C11-C28 polypropionate region of the molecule.
