Heterobinuclear copper(II)-platinum(II) complexes with oxindolimine ligands: Interactions with DNA, and inhibition of kinase and alkaline phosphatase proteins

Author(s)

Aranda, Esther Escribano ^[1] ; da Luz, Juliana Silva ^[2] ; Oliveira, Carla Columbano ^[2] ; Divina Petersen, Philippe A. ^[3] ; Petrilli, Helena M. ^[3] ; da Costa Ferreira, Ana M. ^[1]

Affiliation

^[1] Univ Sao Paulo, Dept Quim Fundamental, Inst Quim, Av Prof Lineu Prestes 748, BR-05508000 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508000 Sao Paulo, SP - Brazil

^[3] Univ Sao Paulo, Inst Fis, Dept Fis Mat & Mecan, BR-05508090 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: Journal of Inorganic Biochemistry; v. 203, FEB 2020.
• Web of Science Citations: 0

Abstract

Two mononuclear copper(II) compounds, {[}Cu(isad)(H2O)Cl]Cl 1 and {[}Cu(isah)(H2O)Cl]Cl 2, and its corresponding heterobinuclear species containing also platinum(II), {[}CuCl(isad)Pt(NH3)Cl-2] 3 and {[}CUCl(isah)Pt (NH3)Cl2] 4 (where isad and isah are oxindolimine ligands, (E)-3-(2-(3-aminopropylamino)ethylimino)indolin-2-one, and (E)-3-(3-amino-2-hydroxypropylimino)indolin-2-one, respectively), have been previously synthesized and characterized by different spectroscopic techniques in our laboratory. Cytotoxicity assays performed with B16F10 murine cancer cells, and MES-SA human uterine sarcoma cells, showed IC50 values lower or in the same order of cisplatin. Herein, in order to better elucidate their probable modes of action, possible interaction and damage to DNA, as well as their effect on the activity of crucial proteins were verified. Both mononuclear complexes and the binuclear compound 4 displayed a significant cleavage activity toward plasmid DNA, while compound 3 tends to protect DNA from oxidative damage, avoiding degradation. Complementary experiments indicated a significant inhibition activity toward cyclin-dependent kinase (CDK1/cyclinB) activity in the phosphorylation of histone H1, and only moderate inhibition concerning alkaline phosphatase. Results also revealed that the reactivity is reliant on the ligand structure and on the nature of the metal present, in a synergistic effect. Simulation studies complemented and supported our results, indicating different bindings of the binuclear compounds to DNA. Therefore, the verified cytotoxicity of these complexes comprises multiple modes of action, including modification of DNA conformation, scission of DNA strands by reactive oxygen species, and inhibition of selected proteins that are crucial to the cellular cycle. (AU)

• FAPESP's process: 11/50318-1 - Development of compounds with pharmacological or medicinal interest and of systems for their transport, detection and recognition in biological media
• Grantee: Ana Maria da Costa Ferreira
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 12/17671-2 - Investigations on the Biological Activity of Heterodinuclear Complexes based on Copper and Platinum
• Grantee: Esther Escribano Aranda
• Support Opportunities: Scholarships in Brazil - Post-Doctoral