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

Abstract

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.

Oxidative Assets Toward Biomolecules and Cytotoxicity of New Oxindolimine-Copper(II) and Zinc(II) Complexes

“…In more recent studies, a significant inhibition of crucial proteins, kinase (CDK1/cyclin B) [31] and topoisomerase IB [32], was additionally verified, emphasizing the contribution of the ligand to the reactivity of such complexes, and their behavior as multifunctional compounds. Interactions of the ligands at the active cavity of the proteins, mostly through hydrogen bonds and stacking, modulate the activity of such complexes [31,32]. These compounds exhibited high thermodynamic stability when tested using human serum albumin (has) as a competitive biological ligand.…”

A small-molecule acts as a ‘roadblock’ on DNA, hampering its fundamental processes

“…Zn-based coordination compounds have been studied for various activities, including toxicity toward infectious organisms [16]. They exhibit more specific functions, such as the inhibition of caspase-3 activity and promotion of ErbB1-ErbB2 heterodimerization by Zinc pyrithione [17], inhibition of cyclin-dependent kinase CDK1 [18]and inhibition of parathyroid hormone activity [13]. Induction of phosphorylation of the Akt downstream effector glycogen synthase kinase 3 and thus proposed to serve as lead structures for developing antidiabetic drugs and useful tools for regulating glucose metabolism to name but a few examples [19].…”

Avaliação da potencialidade e dos mecanismos de ação de complexos dinucleares de cobre como agentes terapêuticos antitumorais

“…Em nossos estudos com complexos de cobre(II) antitumorais, identificamos topoisomerase IB (topo I) [81,82] e quinases dependentes de ciclinas (CDK1 e CDK2) como possíveis alvos [83], além de ácidos nucleicos. Outras proteínas já foram descritas como potenciais alvos, como a proteasoma 26S, em estudos de complexos de cobre(I) com ligantes derivados de tris(pirazolil)borato.…”