JBIC Journal of Biological Inorganic Chemistry

, Volume 20, Issue 7, pp 1205–1217 | Cite as

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

  • Rodrigo Bernardi Miguel
  • Philippe Alexandre Divina Petersen
  • Fernando A. Gonzales-Zubiate
  • Carla Columbano Oliveira
  • Naresh Kumar
  • Rafael Rodrigues do Nascimento
  • Helena Maria PetrilliEmail author
  • Ana Maria da Costa FerreiraEmail author
Original Paper


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.

Graphical Abstract


Oxindolimine-metal complexes Cytotoxicity mechanism Kinase inhibitors Molecular dynamics Molecular docking 



Cyclin-dependent kinase


Density functional theory


Protein data bank


Endoplasmic reticulum kinase


Protein kinase R


Structure activity relationship



This work was supported by Grants from the Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP, Grants 2010/51842-3, 2011/50318-1, and 2013/07937-8), Conselho Nacional de Desenvolvimento Científico Tecnológico (CNPq, Grant 573530/2008-4), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Pro-Reitoria de Pesquisa da Universidade de São Paulo (PRPUSP, Grant 2011.1.9352.1.8). The authors are also grateful to the networks INCT INEO, INCT Redoxoma (FAPESP/CNPq/CAPES), NAP Redoxoma (PRPUSP), CEPID Redoxoma (FAPESP) and BioMol/CAPES (Computational Biology Project). We thank Marcos B. Gonçalves for discussions.

Supplementary material

775_2015_1300_MOESM1_ESM.pdf (1 mb)
Supplementary material 1 (PDF 1026 kb)


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Copyright information

© SBIC 2015

Authors and Affiliations

  • Rodrigo Bernardi Miguel
    • 1
  • Philippe Alexandre Divina Petersen
    • 2
  • Fernando A. Gonzales-Zubiate
    • 3
  • Carla Columbano Oliveira
    • 3
  • Naresh Kumar
    • 1
  • Rafael Rodrigues do Nascimento
    • 2
  • Helena Maria Petrilli
    • 2
    Email author
  • Ana Maria da Costa Ferreira
    • 1
    Email author
  1. 1.Departamento de Química FundamentalInstituto de Química, Universidade de São PauloSão PauloBrazil
  2. 2.Departamento de Física dos Materiais e MecânicaInstituto de Física, Universidade de São PauloSão PauloBrazil
  3. 3.Departamento de BioquímicaInstituto de Química, Universidade de São PauloSão PauloBrazil

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