Inhibition of cyclin-dependent kinase CDK1 by oxindolimine ligands and corresponding copper and zinc complexes

Autor(es)

Miguel, Rodrigo Bernardi ^[1] ; Divina Petersen, Philippe Alexandre ^[2] ; Gonzales-Zubiate, Fernando A. ^[3] ; Oliveira, Carla Columbano ^[3] ; Kumar, Naresh ^[1] ; do Nascimento, Rafael Rodrigues ^[2] ; Petrilli, Helena Maria ^[2] ; da Costa Ferreira, Ana Maria ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Quim, Dept Quim Fundamental, BR-05508000 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Inst Fis, Dept Fis Mat & Mecan, BR-05508090 Sao Paulo, SP - Brazil

^[3] Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508000 Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY; v. 20, n. 7, p. 1205-1217, OCT 2015.
• Citações Web of Science: 9

Resumo

Oxindolimine-copper(II) and zinc(II) complexes that previously have shown to induce apoptosis, with DNA and mitochondria as main targets, exhibit here significant inhibition of kinase CDK1/cyclin B protein. Copper species are more active than the corresponding zinc, and the free ligand shows to be less active, indicating a major influence of coordination in the process, and a further modulation by the coordinated ligand. Molecular docking and classical molecular dynamics provide a better understanding of the effectiveness and kinase inhibition mechanism by these compounds, showing that the metal complex provides a stronger interaction than the free ligand with the ATP-binding site. The metal ion introduces charge in the oxindole species, giving it a more rigid conformation that then becomes more effective in its interactions with the protein active site. Analogous experiments resulted in no significant effect regarding phosphatase inhibition. These results can explain the cytotoxicity of these metal complexes towards different tumor cells, in addition to its capability of binding to DNA, and decreasing membrane potential of mitochondria. (AU)

• Processo FAPESP: 11/50318-1 - Desenvolvimento de compostos com interesse farmacológico ou medicinal e de sistemas para seu transporte, detecção e reconhecimento no meio biológico
• Beneficiário: Ana Maria da Costa Ferreira
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 10/51842-3 - SMOLBNET2: estudo de estrutura de proteínas componentes e reguladoras do exossomo de Archaea e de levedura
• Beneficiário: Carla Columbano de Oliveira
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/07937-8 - Redoxoma
• Beneficiário: Ohara Augusto
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs