RESUMEN
A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. A basic nitrogen within the tether linking the aniline nitrogen atom to a tetrahydroindolone moiety allowed access to compounds with good physical properties. Important structure-activity relationship information was obtained from this series which led to the discovery of a soluble and stable compound which is potent in an Hsp90 binding and cell-proliferation assay.
Asunto(s)
Antineoplásicos/química , Benzamidas/química , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Benzamidas/síntesis química , Benzamidas/farmacología , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular , Simulación por Computador , Cristalografía por Rayos X , Diseño de Fármacos , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Unión Proteica , Relación Estructura-ActividadRESUMEN
The pyranonaphthoquinones (+)-7-deoxyfrenolicin B and (+)-7-deoxykalafungin were synthesized in four steps using an oxa-Pictet-Spengler cyclization that directly provided the natural (3a,5)-trans-substituted dihydronaphthopyrans with high diastereoselectivity. This outcome is in contrast to the unnatural (3a,5)-cis-substituted dihydronaphthopyrans reported under similar conditions for the syntheses of (+)-frenolicin B and (+)-kalafungin. Computational modeling is presented that provides insight into this unusual stereoselectivity.
Asunto(s)
Naftoquinonas/síntesis química , Ciclización , Conformación Molecular , Naftoquinonas/química , EstereoisomerismoRESUMEN
A series of 5-vinyl phenyl sulfonamide-3-pyridinecarbonitriles were prepared and evaluated as PKCtheta inhibitors. Optimization resulted in the identification of compound 15 with an IC(50) value 0.44 nM for the inhibition of PKCtheta with 150-fold selectivity over PKCdelta.
Asunto(s)
Isoenzimas/antagonistas & inhibidores , Proteína Quinasa C/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Piridinas/síntesis química , Piridinas/farmacología , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Diseño de Fármacos , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/química , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
A series of 5-vinyl-3-pyridinecarbonitriles were synthesized and evaluated as PKCtheta inhibitors. The systematic optimization of 4-[(4-methyl-1H-indol-5-yl)amino]-5-[(E)-2-phenylvinyl]-3-pyridinecarbonitrile 3 resulted in the identification of compound 23e as a potent PKCtheta inhibitor with good selectivity over PKCdelta.
Asunto(s)
Isoenzimas/antagonistas & inhibidores , Nitrilos/química , Proteína Quinasa C/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Piridinas/química , Animales , Humanos , Isoenzimas/metabolismo , Microsomas/metabolismo , Nitrilos/síntesis química , Nitrilos/farmacología , Proteína Quinasa C/metabolismo , Proteína Quinasa C-delta/antagonistas & inhibidores , Proteína Quinasa C-delta/metabolismo , Proteína Quinasa C-theta , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
The naturally occurring pyranonaphthoquinone (PNQ) antibiotic lactoquinomycin and related aglycones were found to be selective inhibitors of the serine-threonine kinase AKT. A set of synthetic PNQs were prepared and a minimum active feature set and preliminary SAR were determined. PNQ lactones inhibit the proliferation of human tumor cell lines containing constitutively activated AKT and show expected effects on cellular biomarkers. Biochemical data are presented supporting a proposed bioreductive alkylation mechanism of action.