RESUMEN
Histone deacetylase (HDAC) inhibitors have shown promise in treating various forms of cancer. However, many HDAC inhibitors from diverse structural classes have been associated with QT prolongation in humans. Inhibition of the human ether a-go-go related gene (hERG) channel has been associated with QT prolongation and fatal arrhythmias. To determine if the observed cardiac effects of HDAC inhibitors in humans is due to hERG blockade, a highly potent HDAC inhibitor devoid of hERG activity was required. Starting with dacinostat (LAQ824), a highly potent HDAC inhibitor, we explored the SAR to determine the pharmacophores required for HDAC and hERG inhibition. We disclose here the results of these efforts where a high degree of pharmacophore homology between these two targets was discovered. This similarity prevented traditional strategies for mitigating hERG binding/modulation from being successful and novel approaches for reducing hERG inhibition were required. Using a hERG homology model, two compounds, 11r and 25i, were discovered to be highly efficacious with weak affinity for the hERG and other ion channels.
Asunto(s)
Acrilamidas/toxicidad , Antineoplásicos/toxicidad , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/toxicidad , Ácidos Hidroxámicos/toxicidad , Acrilamidas/síntesis química , Acrilamidas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Canal de Potasio ERG1 , Células HCT116 , Semivida , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacología , Técnicas In Vitro , Ratones , Ratones Desnudos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Trasplante de Neoplasias , Técnicas de Placa-Clamp , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Distribución Tisular , Trasplante HeterólogoRESUMEN
Gamma-hydroxy-alpha,beta-acetylenic esters are used as precursors to prepare gamma-hydroxy-alpha,beta-alkenoic esters by means of trans-selective additions of two hydrogen atoms or one hydrogen atom and one iodine atom across the triple bonds. These methods allow for the preparation of beta-substituted and alpha,beta-disubstituted alkenoic esters in highly stereoselective manners. [reaction--see text]
RESUMEN
Addition of PhLi and lithiated dithianes to 2,3-O-isopropylidene-D-erythronolactone affords lactols, which are reduced with Et3SiH to the corresponding C-glycosides, the structures of two of which have been solved by X-ray diffraction. The use of a d-ribose-derived lithiated dithiane nucleophile in this chemistry allows for the convenient construction of a furanose C-disaccharide.