Pyrazolate-Bridged PdCo and PdCu Complexes as Dual DNA-Binding and ROS-Driven Cytotoxic Agents

Heterometallic complexes offer a promising anticancer strategy owing to their simultaneous action on multiple biological targets. In this work, we report the synthesis and evaluation of the antitumor potential of two heterometallic pyrazolate-bridged complexes, [PdCo(phen)(µ-dmpz)₂(OOCMe)₂] (PdCo) and [PdCu(phen)(µ-dmpz)₂(OOCMe)₂] (PdCu) (phen = 1,10-phenanthroline, dmpz = 3,5-dimethylpyrazole). The complexes were comprehensively characterized using a combined spectroscopic and analytical approach, including single-crystal X-ray diffraction (SC-XRD), PXRD, FTIR, UV-Vis, and mass spectrometry, confirming their structural integrity in both solid state and solution. Their cytotoxicity was assessed in vitro against colon, A549 lung, and breast cancer cell lines, as well as normal human dermal fibroblasts. The complexes exhibited micromolar IC₅₀ values with selectivity indices up to 7. Using circular dichroism (CD) and fluorescence spectroscopy, it was demonstrated that PdCo binds to DNA, with minor groove binding (K_d = 7.6 μM) being the preferred mode of interaction, dominating over intercalation (K_d = 26.1 μM). Molecular docking simulations confirmed that the dissociated [Pd(phen)(µ-dmpz)₂] fragment is capable of binding to DNA. Furthermore, chemiluminescence assays revealed pronounced peroxidase-like and superoxide dismutase-like activities of PdCu and PdCo, implicating ROS-mediated oxidative stress as a second, complementary cytotoxic pathway. Collectively, these findings highlight the dual-action mechanism of the synthesized complexes, combining DNA targeting with ROS-mediated oxidative damage, positioning them as highly potent candidates for further anticancer development.