RESUMEN
Stearoyl-CoA desaturase (SCD) catalyzes the first step in the conversion of saturated fatty acids to unsaturated fatty acids. Unsaturated fatty acids are required for membrane integrity and for cell proliferation. For these reasons, inhibitors of SCD represent potential treatments for cancer. However, systemically active SCD inhibitors result in skin toxicity, which presents an obstacle to their development. We recently described a series of oxalic acid diamides that are converted into active SCD inhibitors within a subset of cancers by CYP4F11-mediated metabolism. Herein, we describe the optimization of the oxalic acid diamides and related N-acyl ureas and an analysis of the structure-activity relationships related to metabolic activation and SCD inhibition.
Asunto(s)
Familia 4 del Citocromo P450/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales/métodos , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Ratones Endogámicos , Ácido Oxálico/química , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Estearoil-CoA Desaturasa/metabolismo , Relación Estructura-ActividadRESUMEN
A novel [3 + 2]-cycloaddition between azomethine imines and lithium ynolates is described to synthesize bicyclic pyrazolidinones. These bicyclic pyrazolidinones are versatile intermediates to form ß-amino acids and monocyclic pyrazolidinones. High diastereoselectivity and stereospecificity allow access to optically active products.
Asunto(s)
Alquinos/química , Compuestos Azo/química , Iminas/química , Pirazoles/síntesis química , Tiosemicarbazonas/química , Catálisis , Reacción de Cicloadición , Estructura Molecular , EstereoisomerismoRESUMEN
A hallmark of targeted cancer therapies is selective toxicity among cancer cell lines. We evaluated results from a viability screen of over 200,000 small molecules to identify two chemical series, oxalamides and benzothiazoles, that were selectively toxic at low nanomolar concentrations to the same 4 of 12 human lung cancer cell lines. Sensitive cell lines expressed cytochrome P450 (CYP) 4F11, which metabolized the compounds into irreversible inhibitors of stearoyl CoA desaturase (SCD). SCD is recognized as a promising biological target in cancer and metabolic disease. However, SCD is essential to sebocytes, and accordingly SCD inhibitors cause skin toxicity. Mouse sebocytes did not activate the benzothiazoles or oxalamides into SCD inhibitors, providing a therapeutic window for inhibiting SCD in vivo. We thus offer a strategy to target SCD in cancer by taking advantage of high CYP expression in a subset of tumors.