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-L_Me)Cl](OTf) (5) and [Pd(o-L′_Me)Cl](OTf) (6), where o-L_Me 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-H₂L_Me(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-H₂L_Me(OTf)₂ (3) and o-H₂L′_Me(OTf)₂ (4). The molecular structure of the palladium complex (5) has been thoroughly analyzed through SC-XRD, revealing a distorted square planar configuration encompassing two five-membered metallacyclic rings. The DFT approach was adopted to meticulously investigate 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⁻¹) and 6 (10⁴ dm³ mol⁻¹). 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 using the MTT protocol on 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.