Development of copper(II)-diimine-iminodiacetate mixed ligand complexes as potential antitumor agents

Author(s)

Alvarez, Natalia ^[1] ; Mendes, Luis F. S. ^[2] ; Gabriela Kramer, M. ^{[3, 4]} ; Torre, Maria H. ^[1] ; Costa-Filho, Antonio J. ^[2] ; Ellena, Javier ^[5] ; Facchin, Gianella ^[1]

Affiliation

^[1] Univ Republica, Fac Quim, Gen Flores 2124, Montevideo - Uruguay

^[2] Univ Sao Paulo, Fac Filosofia Ciencias & Letras Ribeirao Preto, Av Bandeirantes, BR-14040901 Ribeirao Preto, SP - Brazil

^[3] Univ Republica, Fac Quim, Inst Higiene, Lab Carbohydrates & Glycoconjugates, Montevideo 11600 - Uruguay

^[4] Univ Republica, Fac Med, Montevideo 11600 - Uruguay

^[5] Univ Sao Paulo, Inst Fis Sao Carlos, CP 369, BR-13560970 Sao Carlos, SP - Brazil

• Document type: Journal article
• Source: Inorganica Chimica Acta; v. 483, p. 61-70, NOV 1 2018.
• Web of Science Citations: 11

Abstract

In order to seek for new compounds with antitumor activity, our research group is focused on copper complexes with mixed ligands. This work presents the synthesis and characterization of eight compounds with general formula {[}Cu(iminodiacetate)(diimine)(H2O)(x)], with x = 0 or 1, and their cytotoxic activities against tumor cells. The chosen diimine ligands were: 2,2-dipyridil-amine (bam), 2,2-bipyridine (bipy), 4,4-dimethy1-2,2-bipyridine (dmb), 1,10-phenanthroline (phen), 4-methyl-1,10-phenanthroline (4met-phen), 5-nitro-1,10-phenanthroline (5nitro-phen), neocuproine (neo) and bathophenanthroline (batho). Compounds were characterized in solid state using FT-IR, TGA, DSC and single crystal X-ray diffraction analyses by which five new crystal structures were determined. Common features of the coordination scheme include fac-NO + O isomerism of the iminodiacetate (ida) ligand, except for the complex with neo where the ida presents mer-NO2 isomerism. The diimine ligand completes the equatorial plane for the facial isomers, with different degrees of distortion in the octahedral or square-based pyramid geometry depending on the diimine ligand, whereas the neo is perpendicular to the equatorial plane in the latter. Studies in solution, using EPR, UV-Vis spectroscopy and conductimetry, showed that the copper coordination observed in solid state is retained except for the batho complex. DNA interaction studies evidenced that the complexes bind to this biomolecule, inducing different conformational changes. Biological experiments evidenced that all complexes induce cell death in the cell line MDA-MD-231 (metastasic breast cancer line). {[}Cu(ida)(neo)] and {[}Cu(ida)(batho)] presented the highest activity. Taken all these data together we propose that {[}Cu(ida)(neo)] and {[}Cu(ida)(batho)] are good candidates for further studies in vitro and in vivo. (AU)

• FAPESP's process: 12/13309-7 - Structural and functional studies of the Golgi Re-Assembly and Stacking Protein (GRASP) from Cryptococcus neoformans
• Grantee: Luis Felipe Santos Mendes
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 17/24669-8 - Unraveling the molecular bases of the early protein secretory pathway in humans using biophysical techniques
• Grantee: Luis Felipe Santos Mendes
• Support Opportunities: Scholarships in Brazil - Post-Doctoral