Targeting Drug-Resistant Cancer with Copper (II) SchiffBase Complexes

Abstract

Metal-based drugs hold potential as a means to circumvent drug resistance in cancer. In this work، a number of new copper (II) Schiff base complexes with tridentate phenim ligand were prepared and identified by FT-IR، UV-Vis and elemental (CHN) analysis. The spectroscopy indicated that the ligand coordinates to the Cu (II) ion through the azomethine and pyridine nitrogen atoms، resulting in stabler complexes with specific geometries. CuSB-1 [Cu (phenim) Cl₂] was found to be the most active of the compounds synthesized. Cytotoxicity assays showed good anti-proliferative activity against MCF-7, PC3 and HEK-293 cell lines, with significantly lower IC₅₀ values than other complexes and Cisplatin. CuSB-1 was found to effectively interact with DNA, likely via non-covalent binding (intercalation). In vivo studies on a rat breast tumor model demonstrated that CuSB-1 efficiently inhibited tumor growth, lowered specific growth rate and extended the tumor doubling time, surpassing cisplatin. Biochemical and histopathological studies showed increased apoptosis induction and decreased tumor proliferation. Moreover، antioxidant enzyme analysis suggested that CuSB-1 alters the redox balance by reducing the activity of catalase and glutathione peroxidase، and increasing the activity of glutathione reductase، thereby increasing the level of oxidative stress. As a whole, the anticancer effects of CuSB-1 are mediated through a multi-pronged mechanism of action، which includes DNA binding, induction of oxidative stress and activation of apoptosis. The results suggest CuSB-1 could be a lead compound in the development of novel copper-based antitumor drugs.