Synthesis, Characterization and Biological Activity of Novel Cu(II) Complexes of 6-Methyl-2-Oxo-1,2-Dihydroquinoline-3-Carbaldehyde-4n-Substituted Thiosemicarbazones

Molecules. 2020 Apr 17;25(8):1868. doi: 10.3390/molecules25081868.

Abstract

Three new 6-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde-thiosemicarbazones-N-4-substituted pro-ligands and their Cu(II) complexes (1, -NH2; 2, -NHMe; 3, -NHEt) have been prepared and characterized. In both the X-ray structures of 1 and 3, two crystallographically independent complex molecules were found that differ either in the nature of weakly metal-binding species (water in 1a and nitrate in 1b) or in the co-ligand (water in 3a and methanol in 3b). Electron Paramagnetic Resonance (EPR) measurements carried out on complexes 1 and 3 confirmed the presence of such different species in the solution. The electrochemical behavior of the pro-ligands and of the complexes was investigated, as well as their biological activity. Complexes 2 and 3 exhibited a high cytotoxicity against human tumor cells and 3D spheroids derived from solid tumors, related to the high cellular uptake. Complexes 2 and 3 also showed a high selectivity towards cancerous cell lines with respect to non-cancerous cell lines and were able to circumvent cisplatin resistance. Via the Transmission Electron Microscopy (TEM) imaging technique, preliminary insights into the biological activity of copper complexes were obtained.

Keywords: EPR and electrochemical measurements; TEM images; X ray crystal structure; copper thiosemicarbazones complexes; cytotoxicity in 3D spheroids.

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Chemistry Techniques, Synthetic*
  • Coordination Complexes / chemical synthesis*
  • Coordination Complexes / chemistry
  • Coordination Complexes / pharmacology*
  • Copper / chemistry*
  • Electrochemistry
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Structure-Activity Relationship
  • Thiosemicarbazones / chemical synthesis*
  • Thiosemicarbazones / chemistry
  • Thiosemicarbazones / pharmacology*

Substances

  • Antineoplastic Agents
  • Coordination Complexes
  • Ligands
  • Thiosemicarbazones
  • Copper