RESUMEN
c-Met is a transmembrane tyrosine kinase that mediates activation of several signaling pathways implicated in aggressive cancer phenotypes. In recent years, research into this area has highlighted c-Met as an attractive cancer drug target, triggering a number of approaches to disrupt aberrant c-Met signaling. Screening efforts identified a unique class of 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one kinase inhibitors, exemplified by 1. Subsequent SAR studies led to the development of 81 (MK-2461), a potent inhibitor of c-Met that was efficacious in preclinical animal models of tumor suppression. In addition, biochemical studies and X-ray analysis have revealed that this unique class of kinase inhibitors binds preferentially to the activated (phosphorylated) form of the kinase. This report details the development of 81 and provides a description of its unique biochemical properties.
Asunto(s)
Antineoplásicos/síntesis química , Benzocicloheptenos/síntesis química , Piridinas/síntesis química , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Benzocicloheptenos/farmacocinética , Benzocicloheptenos/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Perros , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Haplorrinos , Humanos , Ratones , Ratones Desnudos , Modelos Moleculares , Mutación , Trasplante de Neoplasias , Fosforilación , Unión Proteica , Pirazoles/síntesis química , Pirazoles/farmacocinética , Pirazoles/farmacología , Piridinas/farmacocinética , Piridinas/farmacología , Ratas , Proteínas Tirosina Quinasas Receptoras/genética , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Trasplante HeterólogoRESUMEN
Enantioselective total synthesis of reblastatin is described. The synthesis highlights hydrozirconation, transmetalation, aldehyde addition sequence to install E-trisubstituted olefin and C7 stereocenter, and the first use of an intramolecular Buchwald-like amidation reaction to close the 19-membered macrolactam.
Asunto(s)
Antibacterianos/síntesis química , Quinonas/síntesis química , Antibacterianos/farmacología , Indicadores y Reactivos , Modelos QuímicosRESUMEN
We provide a full account of the discovery of the (E)-9,10-dehydro derivatives of 12,13-desoxyepothilone B (dEpoB), a new class of antitumor agents with promising in vivo preclinical properties. The compounds, which are to date not available by modification of any of the naturally occurring epothilones, were discovered through total chemical synthesis. We describe how our investigations of ring-closing metathesis reactions in epothilone settings led to the first and second generation syntheses of (E)-9,10-dehydro-12,13-desoxyepothilone congener 6. With further modifications, the synthesis was applied to reach a 26-trifluoro derivative compound (see compound 7). To conduct such studies and in anticipation of future development needs, the total synthesis which led to the initial discovery of compound 7 was simplified significantly. The total synthesis methodology used to reach compound 7 was then applied to reach more readily formulated compounds, bearing hydroxy and amino functionality on the 21-position (see compounds 45, 62, and 63). Following extensive in vitro evaluations of these new congeners, compound 7 was nominated for in vivo evaluations in xenograft models. The data provided herein demonstrate a promising therapeutic efficacy, activity against large tumors, nonrelapseability, and oral activity. These results have identified compound 7 as a particularly promising compound for clinical development. The excellent, totally synthetic, route to 7 makes such a program quite feasible.
Asunto(s)
Epotilonas/síntesis química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias del Colon/tratamiento farmacológico , Epotilonas/química , Epotilonas/farmacología , Humanos , Ratones , Mycobacterium/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
There is wide interest in the epothilones, which like the taxoids initiate cytotoxicity through microtubule stabilization. Briefly described is an application of a ring-closing metathesis reaction toward the synthesis of epothilones as carried out in our laboratory. This has led to the discovery of the (E)-9,10-dehydroepothilones as second-generation anticancer drug candidates.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/síntesis química , Epotilonas/química , Epotilonas/síntesis química , Ensayos de Selección de Medicamentos Antitumorales , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , TaxoidesAsunto(s)
Antineoplásicos/síntesis química , Epotilonas/síntesis química , Neoplasias/metabolismo , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Peso Corporal , Ensayos de Selección de Medicamentos Antitumorales , Epotilonas/farmacología , Epotilonas/uso terapéutico , Humanos , Ratones , Ratones Desnudos , Modelos Químicos , Trasplante de Neoplasias , Neoplasias/tratamiento farmacológico , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Relación Estructura-Actividad , Células Tumorales CultivadasAsunto(s)
Epotilonas/química , Epotilonas/síntesis química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Epotilonas/farmacología , Epotilonas/uso terapéutico , Infusiones Intravenosas , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Ratones , Ratones Desnudos , Conformación Molecular , Estructura Molecular , Trasplante de Neoplasias , Factores de TiempoRESUMEN
The total synthesis of a family of (E)-9,10-dehydro derivatives of epothilone D (i.e., 12,13-desoxyepothilone B) is described. The route is particularly concise and amenable to production of new congeners. Furthermore, the chemistry described herein constitutes a major simplification in the total synthesis of EpoD, which is in human clinical trials. This new family of epothilones shows major advantages in terms of their potency and pharmacostability relative to the wild-type saturated analogues in the D series. From the perspective of compound availability through synthesis, potency, and pharmacokinetic properties, these compounds could well warrant advancement to clinical evaluation in humans.