RESUMEN
A novel class of heat shock protein 90 (Hsp90) inhibitors was developed from an unbiased screen to identify protein targets for a diverse compound library. These indol-4-one and indazol-4-one derived 2-aminobenzamides showed strong binding affinity to Hsp90, and optimized analogues exhibited nanomolar antiproliferative activity across multiple cancer cell lines. Heat shock protein 70 (Hsp70) induction and specific client protein degradation in cells on treatment with the inhibitors supported Hsp90 inhibition as the mechanism of action. Computational chemistry and X-ray crystallographic analysis of selected member compounds clearly defined the protein-inhibitor interaction and assisted the design of analogues. 4-[6,6-Dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(trans-4-hydroxycyclohexyl)amino]benzamide (SNX-2112, 9) was identified as highly selective and potent (IC(50) Her2 = 11 nM, HT-29 = 3 nM); its prodrug amino-acetic acid 4-[2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-phenylamino]-cyclohexyl ester methanesulfonate (SNX-5422, 10) was orally bioavailable and efficacious in a broad range of xenograft tumor models (e.g. 67% growth delay in a HT-29 model) and is now in multiple phase I clinical trials.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Descubrimiento de Drogas , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , ortoaminobenzoatos/administración & dosificación , ortoaminobenzoatos/farmacología , Administración Oral , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Disponibilidad Biológica , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos Clínicos como Asunto , Femenino , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Concentración 50 Inhibidora , Ratones , Modelos Moleculares , Conformación Molecular , Profármacos/farmacocinética , Especificidad por Sustrato , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacocinéticaRESUMEN
[reaction: see text] Palladium-catalyzed enantioselective diboration of prochiral allenes generates a reactive chiral allylboron intermediate which is a versatile reagent for the allylation of carbonyls. Experiments that improve the enantioselectivity of this process, examine the substrate scope, and are directed toward functionalization of the allylation intermediate are described.
Asunto(s)
Alcadienos/química , Compuestos de Boro/química , Técnicas Químicas Combinatorias , Paladio/química , Alquilación , Catálisis , Estructura MolecularRESUMEN
Pd-catalyzed diboration of prochiral allenes occurs exclusively at the internal position and is remarkably accelerated in the presence of Lewis basic ligand structures. On the basis of preliminary observations, a chiral ligand was employed, and the enantiomeric excess of a variety of diboration products was found to be in the range of 86-92% ee. The chiral diboron reaction products should be useful in organic synthesis, and preliminary experiments suggest that they may participate in allylation reactions with a high level of chirality transfer.