RESUMO
A novel and straightforward synthesis of highly substituted isoquinoline-5,8-dione fused tricyclic pyrazoles is reported. The key step of the synthetic sequence is a regioselective, Ag2 CO3 promoted, 1,3-dipolar cycloaddition of C-heteroaryl-N-aryl nitrilimines and substituted isoquinoline-5,8-diones. The broad functional group tolerability and mild reaction conditions were found to be suitable for the preparation of a small library of compounds. These scaffolds were designed to interact with multiple biological residues, and two of them, after brief synthetic elaborations, were analyzed by molecular docking studies as potential anticancer drugs. In vitro studies confirmed the potent anticancer effects, showing promising IC50 values as low as 2.5â µm against three different glioblastoma cell lines. Their cytotoxic activity was finally positively correlated to their ability to inhibit PI3K/mTOR kinases, which are responsible for the regulation of diverse cellular processes in human cancer cells.
Assuntos
Antineoplásicos/farmacologia , Benzoquinonas/química , Benzoquinonas/farmacologia , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Sistema Nervoso Central/metabolismo , Neoplasias do Sistema Nervoso Central/patologia , Reação de Cicloadição , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Estrutura Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazóis/síntese química , Pirazóis/química , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismoRESUMO
A series of novel 3,4-disubstituted pyrazoles were synthesized. The cytotoxicity against U87MG glioma cell line have been investigated in vitro and three of these compounds showed promising inhibitory activity on cell growth with an IC50 lower than 90 microM. AutoDock molecular docking into type I TGF-beta receptor (TGF-beta-RI; PDB: 1py5) has been done for lead optimization of the mentioned compounds as potential TGF-beta-RI1 inhibitors. In particular, 3-aryl-4-amido pyrazole containing long omega-amino-aliphatic chain emerged as a good candidate for further optimization. Entrapment into targetable PEG-based micelles improved growth inhibition IC50 values up to 100 nM and this could lead to a novel drug delivery strategy for treating glioblastoma.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Desenho de Fármacos , Glioma/tratamento farmacológico , Nanomedicina , Pirazóis/síntese química , Pirazóis/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Glioma/metabolismo , Glioma/patologia , Humanos , Micelas , Modelos Químicos , Estrutura Molecular , Pirazóis/química , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The palladium-catalyzed desilylation-arylation of substituted vinylsilanes by p-iodoanisole in the presence of bidentate phosphine ligands is described. Apart from enhancing the rate of the reaction considerably, heteroatom-based functional groups in the vinylsilane moiety have a profound influence on the regiochemistry. A catalytic cycle for the chelation-controlled desilylation-arylation reaction involving five- and six-membered chelate rings is proposed.
