Water Soluble Palladium Complexes Bearing NNN-Pincer Ligands: Synthesis, DFT Modeling, cT-DNA Interactions and In Vitro Cytotoxicity Studies Against Breast Cancer Cell Lines

Abstract

In the pursuit of designing new anticancer pharmaceuticals and enhancing the therapeutic effectiveness of metal-containing compounds, two new Pd(II) pincer complexes, [Pd(o-LMe)Cl](OTf) (5) and [Pd(o-L′Me)Cl](OTf) (6), where o-LMe is (N2Z,N6Z)-N2,N6-bis(1-methylpyridin-2(1H)-ylidene)pyridine-2,6-dicarboxamide and o-L′Me is (N2Z,N6Z)-N2,N6-bis(1,4-dimethylpyridin-2(1H)-ylidene)pyridine-2,6-dicarboxamide commonly known as pyridylidene amide (PYA) ligands, were successfully synthesized and subjected to characterization through various spectroscopic methodologies. The PYA ligands were generated from proligands, o-H2LMe(OTf)2 (3) and o-H2L′Me(OTf)2 (4) during the complexation reaction. The precursors, 1 (o-H2L) and 2 (o-H2L′), were synthesized by treatment of dipicolinic acid with 2-aminopicoline and 2-amino-4-methylpicoline, respectively, in the presence of triphenyl phosphite followed by methylation to obtain o-H2LMe(OTf)2 (3) and o-H2L′Me(OTf)2 (4). The molecular structure of palladium complex (5)has been thoroughly analyzed through the SC-XRD, revealing a distorted square planar configuration encompassing two five-membered metallacyclic rings. The DFT approach meticulously investigated the electronic features, molecular electrostatic potential, and frontier molecular orbitals of the complexes. The nature of the compound’s interaction with cT-DNA and the implications of pincer-PYA coordination on the binding affinity of Pd(II) complexes were probed through UV-visible spectrophotometry and viscometry. The results elucidated the intercalative mode of interaction alongside elevated binding parameters for 5 (105 dm3/mol) and 6 (104 dm3/mol). Molecular docking of complex 5 was performed, which exhibited a strong interaction with DNA and supported the experimental findings. The in vitro cytotoxic effects of the samples were systematically assessed by MTT protocol on the breast cancer (MCF-7 and T47D) and normal (Vero) cell lines. According to the determined IC50 values, Pd(II) complexes demonstrated a prominent influence in augmenting cytotoxicity. The cytotoxicity values associated with these compounds follow a hierarchy of 5 > cisplatin > 6 > 4 > 3 within neoplastic cells. The apoptotic effects of 5 and 6 on the MCF-7 cancer cell line were examined to elucidate the mechanistic pathway responsible for its maximal cytotoxic efficacy.