RESUMEN
We herein report the synthesis, biological activity and preliminary structure-activity relationships of a series of diaryl[1,3]diazepines. These compounds were able to inhibit the proliferation of many cancer cell lines, such as HeLa, MCF-7, SGC7901 and A549. When HeLa cells were treated with lead compounds 7j and 7k at 3 [Formula: see text] concentration, cell arrest was observed in the G2/M phase.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Azepinas/síntesis química , Azepinas/farmacología , Antineoplásicos/química , Azepinas/química , Técnicas de Química Sintética , Células HeLa , Humanos , Relación Estructura-ActividadRESUMEN
A series of novel and diverse diaryl[d,f][1,3]diazepines were designed and synthesized to expand the pharmaceutical utility of the [6,7]bicyclic molecular skeletons. The facile synthesis involved two key steps: a one-pot Suzuki coupling to construct the bi-aryl intermediates from corresponding halides, and a ring closure by direct condensation with carboxylic acids.
Asunto(s)
Azepinas/química , Azepinas/síntesis química , Ácidos Carboxílicos/química , Técnicas de Química SintéticaRESUMEN
The discovery of two classes of pyrimidine-based inhibitors of GSK-3 is described. Optimization of these series led to inhibitors with IC(50)<10nM and >100-fold selectivity over Aurora A kinase. A proposed binding mode of 21b is presented. One compound (33) of the pyrimidine series showed promising pharmacokinetic parameters.
Asunto(s)
Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Purinas/farmacología , Pirimidinas/farmacología , Administración Oral , Animales , Aurora Quinasa A , Aurora Quinasas , Sitios de Unión , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Enlace de Hidrógeno , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Purinas/síntesis química , Purinas/química , Pirimidinas/síntesis química , Pirimidinas/química , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
Type II diabetes mellitus is a chronic metabolic disorder that can lead to serious cardiovascular, renal, neurologic, and retinal complications. While several drugs are currently prescribed to treat type II diabetes, their efficacy is limited by mechanism-related side effects (weight gain, hypoglycemia, gastrointestinal distress), inadequate efficacy for use as monotherapy, and the development of tolerance to the agents. Consequently, combination therapies are frequently employed to effectively regulate blood glucose levels. We have focused on the mitochondrial sodium-calcium exchanger (mNCE) as a novel target for diabetes drug discovery. We have proposed that inhibition of the mNCE can be used to regulate calcium flux across the mitochondrial membrane, thereby enhancing mitochondrial oxidative metabolism, which in turn enhances glucose-stimulated insulin secretion (GSIS) in the pancreatic beta-cell. In this paper, we report the facile synthesis of benzothiazepines and derivatives by S-alkylation using 2-aminobenzhydrols. The syntheses of other bicyclic analogues based on benzothiazepine, benzothiazecine, benzodiazecine, and benzodiazepine templates are also described. These compounds have been evaluated for their inhibition of mNCE activity, and the results from the structure-activity relationship (SAR) studies are discussed.