Abstract
A new ligand, benzylidene-phenol-thiazole (HBHTP), and its M(ii) complexes (M = Co, Ni, Cu, or Zn) were synthesized using a hybrid pharmacophore approach. The structures were optimized using density functional theory (DFT) calculations. MTT cytotoxicity assay showed that CuBHTP was the most effective and least toxic to normal cells, with the highest toxicity against MCF-7 cells. CuBHTP was more selective than staurosporine, with a selectivity index (SI) of 4.2 for cancer MCF-7 cells compared to 2.5 for healthy MCF10a cells. Compared with novobiocin, it exhibited significant inhibitory effects on aromatase cytochrome 19A and reduced Hsp90 expression. The treatment also revealed significant upregulation of the apoptotic marker P53 and inhibitory effects on tubulin β, SULF1,2, and bFGF gene expression levels compared to the untreated MCF7 carcinoma. Furthermore, CuBHTP significantly inhibited topoisomerase I and cell proliferation by inducing cell cycle arrest in G1 and S phases. The CuBHTP complex is a highly effective anticancer agent, and molecular docking studies have confirmed its binding to grooves and topoisomerase I. Therefore, ligand/copper may shed new light on the inhibitory mechanisms of cancer cell proliferation through its ability to form DNA adducts.