Biological effects of p-PYA ligands on certain trace elements of group-12 towards DNA binding and cytotoxicity...

The substantial anticancer potential of inexpensive trace metal-based coordination compounds has been seen to convey enormous significance in the area of cancer therapy. Herein, the present work portrays the synthesis of four new Cd(II) and Zn(II) complexes of general formula, $\left[\text{M}\left({\text{L}}_{\text{R}}^{\text{p}}\right){\left(\text{X}\right)}_2\right]$ , where M = Zn(II) or Cd(II) and X = I^- or Cl^-, encompassing the pincer-shaped pyridylidene amide derivatives of ${\text{L}}_{\text{Me}}^{\text{p}}$  = N²,N⁶-bis(1-methylpyridin-4(1H)-ylidene)pyridine-2,6-dicarboxamide and ${\text{L}}_{\text{Bn}}^{\text{p}}$  = N²,N⁶-bis(1-benzylpyridin-4(1H)-ylidene)pyridine-2,6-dicarboxamide. The synthesized drug candidates were characterized through NMR (¹H and ¹³C), FT-IR spectroscopy and elemental analysis. Geometry optimization, frontier orbital analysis and electronic characteristics were investigated by DFT studies. Compounds 1-7 interacted with DNA, showing moderate binding affinity to CT DNA (K_b = 1.8 to 9.4 × 10⁴ M^-1) and stabilizing the duplex through mixed binding mechanisms, supported by molecular docking studies. Complexes (4-7) were determined to be stable during the examined time by using electronic spectroscopy and ¹HNMR analysis of their solutions. The MTT assay was used to evaluate the cytotoxicity of ligands and complexes. The Annexin V-FITC apoptosis detection and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays were used to assess early apoptosis and DNA fragmentation, respectively. By employing the Caspase-Glo™ assay to investigate pro-apoptotic caspase activation, the fundamental mechanism of DNA fragmentation was further clarified. The in vitro cytotoxicity of the compounds was evaluated against breast cancer cell lines (MCF-7, T47D) and the Vero cell line as a representative of normal cells. Complexes 6 (12.2 ± 0.3 µM) and 7 (10.0 ± 3.6 µM) exhibited remarkable anticancer activity compared to complexes 4 (40.0 ± 0.8 µM), 5 (29.0 ± 2.8 µM), and cisplatin (25.1 ± 1.1 µM) against the T47D cell line. Furthermore, complexes 6 and 7 induced DNA fragmentation through the initiation of early and late apoptosis, accompanied by the activation of apoptotic signaling cascades (caspase-3/7 and caspase-9), thereby confirming apoptosis as the underlying mechanism of cell death in the breast cancer cell line.