Design of DNA-intercalators based copper(II) complexes, investigation of their potential anti-cancer activity and sub-chronic toxicity

In the present paper, we synthesized and characterized four N-donor polypyridyl copper(II) complexes (C1-C4); [Cu(mono-CN-PIP)2]2+ (C1), [Cu(tri-OMe-PIP)2]2+ (C2), [Cu(di-CF3-PIP)2]2+ (C3) and [Cu(DPPZ)2]2+ (C4). The (Calf-Thymus) CT-DNA binding studies depicted that the complexes could interact with DNA via intercalative mode. All the complexes, particularly C3 and C4 attenuated the proliferation as well as migration of various cancer cells, indicating their anti-cancer and anti-metastatic activity. Additionally, chick embryo angiogenesis (CEA) assay exhibited the inhibition of vascular sprouting in presence of C3 and C4, suggesting their potential in inhibiting the blood vessel growth. Mechanistic studies revealed that the complexes induced the excessive production of cellular reactive oxygen species (ROS) leading to apoptosis through up regulation of p53 and downregulation of Bcl-xL, which might be the plausible mechanisms underlying their anti-cancer properties. To understand the feasibility of practical application of anti-cancer copper complexes C3 and C4, in vivo sub-chronic toxicity study (4 weeks) was performed in C57BL6 mice and the results exhibited almost non-toxic effects induced by these complexes in terms of haematology and serum biochemical analyses, suggesting their biocompatible nature. The current study provides the basis for future advancement of other novel biocompatible metal complexes that could be employed for the therapy of different cancers. Schematic overview of plausible mechanism underlying the anti-cancer properties of copper (II) polypyridyl complexes. [Display omitted] •Synthesis and characterizations of four N-donor polypyridyl copper(II) complexes (C1-C4).•Strong binding of the complexes with CT-DNA through intercalative mode.•Excellent anti-cancer activity of C1-C4 in three different types of cancer cells (B16F10, MDA-MB-231, SKOV3).•The complexes also possess the ability to attenuate the migration of cancer cells as evidenced by scratching assay.•Mechanistic investigation revealing the activation of apoptosis of cancer cells.•Western blot analysis exhibiting upregulation of apoptotic p53 protein and downregulation of anti-apoptotic Bcl-xL protein.•Feasibility for the practical biomedical applications with biocompatible nature observed through sub-chronic toxicity.