RESUMO
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.
Assuntos
Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/química , Pirimidinonas/química , Inibidores da Transcriptase Reversa/química , Timina/análogos & derivados , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Sítios de Ligação , Cristalografia por Raios X , Cães , Transcriptase Reversa do HIV/metabolismo , Humanos , Microssomos/metabolismo , Pirimidinonas/síntese química , Pirimidinonas/farmacocinética , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacocinética , Relação Estrutura-Atividade , Timina/síntese química , Timina/química , Timina/farmacocinéticaRESUMO
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.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Isoquinolinas/farmacocinética , Isoquinolinas/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.