Triple-negative breast cancer (TNBC) remains one of the most aggressive and challenging forms of breast cancer, characterized by a lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. This absence limits therapeutic options and contributes to high rates of metastasis and poor prognosis. The current standard treatment relies heavily on platinum-based chemotherapeutics such as cisplatin, carboplatin, and oxaliplatin; however, their clinical utility is hampered by severe side effects including nephrotoxicity, neurotoxicity, and drug resistance. In response, researchers have turned toward non-platinum metal complexes, particularly those based on nickel and palladium—elements in the same group as platinum—with the aim of developing agents that retain antitumor efficacy while reducing toxicity.
This study focuses on a series of S,C,S-type pincer complexes of nickel and palladium featuring a central meta-phenylene backbone and two labile thioamide donor groups at the periphery. These ligands are designed to promote chelation through sulfur atoms, forming stable tridentate coordination environments around the metal center. The synthesized complexes include L1NiCl, L1NiBr, L1PdCl, L2PdCl, and L3PdCl, all of which were evaluated for their cytotoxic effects against hormone-responsive (MCF-7 and MC4L2) and triple-negative (4 T1) breast cancer cell lines. Results revealed that palladium complexes exhibited significantly higher selectivity and lower toxicity toward normal cells compared to their nickel analogues, making them promising candidates for further investigation.
Among the tested compounds, L3PdCl—bearing a morpholine-containing thioamide ligand—showed the most potent activity against 4 T1 TNBC cells with an IC50 value of 10 µM after 48 hours of exposure. Furthermore, this complex demonstrated strong inhibition of both cell adhesion and migration in vitro, key processes involved in cancer metastasis. The scratch-wound assay confirmed that palladium complexes markedly reduced the migratory capacity of 4 T1 cells, suggesting their potential to impede tumor spread. Notably, L2PdCl, which contains a piperidine moiety, also displayed high potency even at short incubation times (24 h), indicating rapid biological action.
Structural analysis via X-ray crystallography confirmed the square planar geometry of the metal centers in these complexes, with Ni–C(aryl) bond lengths ranging from 1.86 to 1.87 Å and M–X (X = Cl, Br) distances consistent with typical coordination behavior. Electronic spectroscopy revealed intense absorption bands at ~249 nm (LC transition) and ~475 nm (d–d transition), supporting the presence of low-spin Ni(II) and Pd(II) centers.MFGE8 Antibody supplier UV-vis data, combined with NMR studies, confirmed successful C–H metallation during synthesis and the dynamic equilibrium between halide-ligated and solvent-exchanged species in solution.KYNU Antibody References
Density functional theory (DFT) calculations provided insight into reactivity patterns.PMID:35202894 HOMO and LUMO energy levels indicated moderate electron transfer capability, with small band gaps (0.23–0.25 eV) suggesting enhanced chemical reactivity. The HOMO was localized primarily on the metal center and sulfur donors, while the LUMO resided mainly on the aryl ring and CS–N fragment, indicating charge transfer pathways conducive to DNA interaction. Global electrophilicity and hardness values further supported the potential for target binding.
In conclusion, this work demonstrates that palladium-based S,C,S pincer complexes exhibit superior cytotoxic profiles and reduced off-target toxicity compared to nickel analogues. Their ability to inhibit proliferation, adhesion, and migration of TNBC cells underscores their promise as next-generation anticancer agents. Future studies should explore in vivo efficacy, pharmacokinetics, and mechanisms of DNA interaction, particularly focusing on intercalative binding driven by planar molecular architecture. These findings open new avenues for rational design of metal-based therapeutics targeting aggressive, treatment-resistant cancers like TNBC.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com
