SYNTHESIS, IN VITRO, AND IN SILICO ANTI-CANCER STUDIES OF SUBSTITUTED BENZIMIDAMIDE AND ITS CU(II) COMPLEX

Copper complexes have a remarkable identity in the hope of curing cancer. In search of a non-toxic anticancer agent, a new ligand (N-(2-amino-4-bromophenyl)-4-fluoro-N'-(2-fluorophenyl)benzimidamide) having famous medicinal moiety, "benzimidamide" was synthesized for complexation with Copper. The synthesis of compounds was confirmed by FT-IR, multinuclear (H-1, C-13) NMR spectroscopy. The carbon, hydrogen, and nitrogen composition were determined by CHN analysis. The compounds were also characterized by UV-vis, PXRD, and thermal (TGA/DTA) analysis. The absorption spectral titration experiments suggest that the ligand and its Cu(II) complex are bound to DNA through intercalation mode but Cu(II) complex is a good partial intercalator having a binding constant of less than 10(6) M-1, which was further verified by viscometry. The Cu(II) complex showed meagre nuclease activity as compared to ligand, in the absence of oxidant. However, the activity was improved in the presence of an oxidant expedited by the generation of hydroxyl free radicals. The reduced level of toxicity parameters in liver and kidney function tests is a clear indication of the nontoxic nature of the ligand and its Cu(II) complex. The cytotoxic effect on MDA-MB-231, MCF-7, WRL-68 and MCF-10A cell lines was observed and we found that Cu(II) complex is more active than the ligand against the cancer cell lines and remains inactive against human normal MCF-10 breast cells and WRL-68 hepatic cells. All the findings suggest that both the ligand and Cu(II) complex could bind with DNA, cleave DNA via intracellular reactive oxygen species, defunctionalize mitochondria, arrest the cell cycle and stimulate the programmed cell death. As a result of the docking process on human serum albumin (PDB code: 1AO6), it was found that the ligand and its Cu(II) complex have a higher affinity for human serum albumin. Cu(II) complex was found to have the least docking energy (-7.1 Kcal mol(-1)).