RESUMO
A series of new ureidoindolin-2-one derivatives were synthesized and evaluated as inhibitors of receptor tyrosine kinases. Investigation of structure-activity relationships at positions 5, 6, and 7 of the oxindole skeleton led to the identification of 6-ureido-substituted 3-pyrrolemethylidene-2-oxindole derivatives that potently inhibited both the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) families of receptor tyrosine kinases. Several derivatives showed potency against the PDGFR inhibiting both its enzymatic and cellular functions in the single-digit nanomolar range. Among them, compound 35 was a potent inhibitor against tyrosine kinases, including VEGFR and PDGFR families, as well as Aurora kinases. Inhibitor 36 (non-substituted on the pyrrole or phenyl ring) had a moderate pharmacokinetic profile and completely inhibited tumor growth initiated with the myeloid leukemia cell line, MV4-11, in a subcutaneous xenograft model in BALB/c nude mice.
Assuntos
Receptores ErbB/antagonistas & inibidores , Indóis/química , Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirróis/química , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Ureia/análogos & derivados , Animais , Aurora Quinases , Sítios de Ligação , Linhagem Celular Tumoral , Simulação por Computador , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/metabolismo , Humanos , Indóis/uso terapêutico , Indóis/toxicidade , Leucemia Mieloide/tratamento farmacológico , Camundongos , Oxindóis , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/toxicidade , Proteínas Serina-Treonina Quinases/metabolismo , Pirróis/uso terapêutico , Pirróis/toxicidade , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Relação Estrutura-Atividade , Transplante Heterólogo , Ureia/química , Ureia/uso terapêutico , Ureia/toxicidadeRESUMO
Spiro derivatives of oxindole and isoxazole-5-one were synthesized by using Michael addition reaction, highlighting the regioselective approach towards the synthesis of Michael diadduct followed by condensation of Michael diadduct. The spiro compound 4 showed antitubercular activity against Mycobacterium tuberculosis H37Rv whereas spiro compound 9 possesses pronounced anticancer and antibacterial profile.