Synthesis, crystal structure, DNA/protein interactions and cytotoxicity studies of tridentate ligand based Cu(II) complexes with various amine co-ligands

Abstract

The present study utilizes a tridentate ligand H₂L (1) derived as a condensation product of dehydroacetic acid and 2-furoic acid hydrazide for the synthesis of a series of copper complexes, namely [Cu(L)(bipy)] (3), [Cu(L)(4,4′-Me₂-bipy)] (4), [Cu(L)(6,6′-Me₂-bipy)] (5), [Cu(L)(phen)] (6), [Cu(L)(2,9-Me₂-phen)] (7) [Cu(L)(pyrazino[2,3]phen)] (8) [Cu(L)(2,2′-dipyridylamine)] (9) [Cu(L)(diphenylmethanamine)] (10), obtained by reacting Cu(acetate)₂ with the doubly deprotonated ligand and a range of co-ligand amines. All the synthesized compounds were fully structurally characterized using IR, ¹H NMR, HRMS and single-crystal X-ray diffraction studies. The thermal stability and decomposition pattern was investigated using TGA studies. The bio-efficacy of the developed ligand and its complexes was evaluated in anti-cancer assay against SKOV3 cell lines. Copper complexes have been extensively studied for their potential to generate anticancer properties. Most complexes comprise mixed ligands, such as N-N-chelating heterocycles like 2,2’-bipyridine (bpy) and 1,10 phenanthroline (phen), chosen for their chelating and intercalative characteristics. Complex 7 displayed the highest anti-cancer activity with an IC₅₀ value of 0.8 µM compared to standard drug doxorubicin. The impact of complex 7 on DNA fragmentation was also assessed through agarose gel electrophoresis, which indicated that complex 7 promotes observable DNA fragmentation. The serum binding affinity of the complex 7 was also investigated against BSA and HSA protein. The strong binding affinity of complex [Cu(L)(2,9-Me2-phen)] (7) with BSA/HSA and its better stability compared to the other investigated complexes were deduced based on its biological activity. The impact of varying concentrations of complex 7 on BSA and HSA was investigated using absorption spectroscopy, revealing the presence of a dynamic quenching mechanism. In silico molecular dynamics and docking, approaches have been utilized to validate the empirical data derived from serum binding studies.