Energetically significant antiparallel π-stacking contacts in Co(II), Ni(II) and Cu(II) coordination compounds of pyridine-2,6-dicarboxylates: Antiproliferative evaluation and theoretical studies

Three new coordination compounds of types [Co(py)(2,6-PDC)(H2O)(2)]center dot H2O (1), [Ni(py)(2,6-PDC(H2O)]center dot 2H(2)O (2) and [Cu(py)(2,6-PDC)(H2O)]center dot 2H(2)O (3) (py = pyridine, 2,6-PDC = Pyridine-2,6-dicarboxylate) have been synthesized from purely aqueous media and characterized using elemental analysis, spectroscopic (IR and electronic) and single crystal X-ray diffraction techniques. Several supramolecular contacts of types O-H center dot center dot center dot O, C-H center dot center dot center dot O, C-H center dot center dot center dot pi, C-H center dot center dot center dot C and pi-pi stacking stabilize the crystal structures. The layers in the crystal structures stack in perpendicular direction resulting in 1D channel with enclathrated water molecules. The strength of the antiparallel pi-stacking interactions involving the pyridine rings in the supramolecular dimer of the compounds have been evaluated using DFT calculations and the influence of the pyridine coordination to the strength of the stacking assembly have been confirmed. The anti-proliferative potential of the compounds has been studied in Dalton's lymphoma (DL) cell line by using MTT cell viability assay and apoptosis assay. All the three complexes exhibit short term (24 h) cytotoxicity (similar to 20-30%) through apoptotic cell death with negligible cytotoxicity (similar to 5-10%) in normal cells. In silico docking simulation has been performed with apoptosis regulator protein BCL-2 for the identification of possible molecular mode of action of the synthesized complexes. The pharma-cophore features based on structure activity relationship (SAR) of the complexes have been identified. The SAR results reveal that the molecular features such as, hydrophobic, aromatic, positive ionizable, negative ionizable, H-bond donor and acceptor and halogen bond donor associated with the structures of the compounds play important role in the biological activities. The ADMET features, viz., physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness of the synthesized complexes have been investigated.