RESUMO
To develop multikinase inhibitors with dual PLK1/VEGF-R2 inhibitory activity, the d-annulated 1-benzazepin-2-one scaffold present in the paullone family of kinase inhibitors was investigated as a general structure template suitable for anchoring annulated heterocycles at the hinge region of the ATP binding site. For this purpose, the indole substructure of the paullones was replaced by other nitrogen containing heteroaromatics. The designed scaffolds were synthesized and tested on the indicated kinases. The 2-anilino-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-ones were found to be VEGF-R2 inhibitors with selectivity against the insulin receptor kinase. The attachment of a methoxy group to the 9-position of the scaffold led to additional PLK1 inhibitory activity, which was explained by an alternative binding mode of the 9-methoxy derivatives. Selected members of the compound class inhibited the VEGF-R2 autophosphorylation in human umbilical vein endothelial cells, the sprouting of human umbilical vein endothelial cell speroids, and the proliferation of diverse cancer cell lines.
Assuntos
Benzazepinas/química , Benzazepinas/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pirimidinas/química , Pirimidinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sítios de Ligação , Ligação Competitiva , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas/química , Proteínas Proto-Oncogênicas/metabolismo , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Quinase 1 Polo-LikeRESUMO
A collection of paullones was tested for inhibitory activity against mitochondrial malate dehydrogenase (mMDH) as a biological target for antiproliferative activity. Based on the results of this screening, 5-benzylpaullones and paullone-9-carboxylic acid alkyl esters were developed as selective mMDH inhibitors. The new derivatives did not show noteworthy antiproliferative activity when tested on a panel of cancer cell lines, suggesting that mMDH inhibition is of minor relevance for the growth inhibition caused by paullones.
Assuntos
Benzazepinas/síntese química , Benzazepinas/farmacologia , Ácidos Carboxílicos/química , Descoberta de Drogas , Malato Desidrogenase/antagonistas & inibidores , Mitocôndrias/enzimologia , Benzazepinas/química , Linhagem Celular Tumoral , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Especificidade por SubstratoRESUMO
The synthesis of 1-aryl-4,6-dihydropyrazolo[4,3-d][1]benzazepin-5(1H)-ones by cyclization of 4-[(dimethylamino)methylidene]-3,4-dihydro-1H-[1]benzazepine-2,5-dione with arylhydrazines is reported. When tested on a panel of human cancer cell lines, the title compounds showed antiproliferative activity and a characteristic selectivity pattern of growth inhibition. Although structurally akin to established kinase inhibitors, the new compounds did not exhibit noteworthy inhibitory activity when tested on an array of cancer-related kinases.
