RESUMEN
A series of N1-alkyl pyrimidinediones were designed, synthesized and evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Our efforts identified compound 10b, which represents the lead compound in this series with pharmacokinetics and antiviral potency that may support once-daily dosing.
Asunto(s)
Fármacos Anti-VIH/química , Transcriptasa Inversa del VIH/química , Pirimidinonas/química , Inhibidores de la Transcriptasa Inversa/química , Timina/análogos & derivados , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacocinética , Sitios de Unión , Cristalografía por Rayos X , Perros , Transcriptasa Inversa del VIH/metabolismo , Humanos , Microsomas/metabolismo , Pirimidinonas/síntesis química , Pirimidinonas/farmacocinética , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacocinética , Relación Estructura-Actividad , Timina/síntesis química , Timina/química , Timina/farmacocinéticaRESUMEN
Novel analogs of (-)-saframycin A are described. The analogs are shown to be potent inhibitors of the in vitro growth of several tumor cells in a broad panel and promising as leads for further optimization. The first in vivo studies in a solid tumor model (HCT-116) reveal potent antitumor activity with associated toxicity of daily administration.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Isoquinolinas/síntesis química , Isoquinolinas/química , Isoquinolinas/farmacocinética , Isoquinolinas/farmacología , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
As a continuation of our efforts to discover novel apoptosis inducers as anticancer agents using a cell-based caspase HTS assay, 2-phenyl-oxazole-4-carboxamide derivatives were identified. The structure-activity relationships of this class of molecules were explored. Compound 1k, with EC(50) of 270 nM and GI(50) of 229 nM in human colorectal DLD-1 cells, was selected and demonstrated the ability to cleave PARP and displayed DNA laddering, the hallmarks of apoptosis. Compound 1k showed 63% tumor growth inhibition in human colorectal DLD-1 xenograft mouse model at 50 mpk, bid.