RESUMO
The bis-indole indigoids are a promising protein kinase inhibitor scaffold to be further evaluated against the numerous human diseases that imply abnormal regulation of kinases including neurodegenerative disorders. In an effort to identify new pharmacological inhibitors of disease-relevant protein kinases with increased potency and selectivity, we designed, synthesized new 5,7-disubstituted or 6-substituted bis-indole derivatives. On the basis of our previous synthetic work, 22 selected compounds were tested on CDK1/cyclin B, CDK5/p25, DYRK1A, CK1, and GSK-3alpha/beta kinases, five kinases involved in Alzheimer's disease. Some of them were also evaluated for their cytotoxic and antiproliferative activities. 6-Nitro-3'-N-oxime-indirubin and 5-amino-3'-N-oxime-indirubin derivatives exhibited inhibitory activity in a submicromolar range against CDK1/cyclin B (0.18 and 0.1 microM, respectively), CK1 (0.6 microM and 0.13 microM) and GSK3 (0.04 microM and 0.36 microM).
Assuntos
Ciclina B1/antagonistas & inibidores , Indóis/síntese química , Fármacos Neuroprotetores/síntese química , Inibidores de Proteínas Quinases/síntese química , Proteínas Quinases/química , Doença de Alzheimer/tratamento farmacológico , Caseína Quinase I/antagonistas & inibidores , Caseína Quinase I/metabolismo , Ciclina B1/metabolismo , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Quinase 5 Dependente de Ciclina/metabolismo , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Indóis/química , Indóis/toxicidade , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/toxicidade , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/toxicidade , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Quinases DyrkRESUMO
The biological evaluation of some novel thiazoloindolo[3,2-c]quinoline, 8-substituted-11H-indolo[3,2-c]quinolines is described. These compounds were obtained via Graebe-Ullmann thermal cyclization from appropriated N-arylated benzotriazoles. 7H-4,7-Diaza-benzo[de]anthracene, a reaction by-product structurally closed to the pyridoacridine skeleton was also identified. All thiazolobenzotriazole intermediates were tested in vitro for their capacity to inhibit the growth of two breast cancer cell lines, MCF-7 and MDA-MB-231. In parallel, the newly synthesized skeletons were evaluated for DNA interaction, topoisomerases' inhibition, and cytotoxicity against HL60 and HL60/MX2 human leukemia cells. Most compounds showed a potent growth inhibitory effect on all the tested cell lines, with IC(50) in the muM range.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Triazóis/química , Triazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA/metabolismo , DNA Topoisomerases Tipo I/metabolismo , Feminino , Humanos , Indóis/química , Leucemia/tratamento farmacológico , Quinolinas/síntese química , Quinolinas/toxicidade , Tiazóis/química , Inibidores da Topoisomerase I , Triazóis/síntese química , Triazóis/toxicidadeRESUMO
In an effort to identify new pharmacological inhibitors of disease-relevant protein kinases with increased potency and selectivity, we synthesized and evaluated new 5-substituted indirubins. The effects of 34 indirubin derivatives on CDK1/cyclin B, CDK5/p25, and GSK-3, as well as on SH-SY5Y human neuroblastoma cell survival, were investigated.