Synthesis, structural topologies and anticancer evaluation of phenanthroline-based 2,6-pyridinedicarboxylato Cu(II) and Ni(II) compounds

• Published in: Polyhedron 2022-02, Vol.213, p.115632, Article 115632
• Main Authors: Das, Amal, Sharma, Pranay, Gomila, Rosa M., Frontera, Antonio, Verma, Akalesh K., Sarma, Bipul, Bhattacharyya, Manjit K.
• Format: Article
• Language: English
• Subjects: Apoptosis; Cytotoxicity; Dinuclear; Docking; Structural topologies
• ISSN: 0277-5387
• DOI: 10.1016/j.poly.2021.115632

Synthesis, supramolecular assemblies, in vitro antiproliferative activities and structure activity relationships of phenanthroline-based 2,6-pyridinedicarboxylato Cu(II) and Ni(II) compounds were investigated, including cell cytotoxicity, apoptosis assay, molecular docking and pharmacophore studies. [Display omitted] Two new coordination compounds of Cu(II) and Ni(II), viz. [Cu2(phen)(μ-2,6-PDC)(2,6-PDC)(H2O)2]·4·.5H2O (1) and [Ni(phen)(2,6-PDC)(H2O)]·2H2O (2) (phen = 1,10-phenanthroline; 2,6-PDC = 2,6-pyridinedicarboxylate), have been synthesized under ambient conditions and further characterized using single crystal X-ray diffraction, FTIR, electronic spectroscopy, thermal and elemental analysis. The compound 1 is a 2,6-PDC bridged dinuclear Cu(II) compound, whereas compound 2 crystallizes as a mononuclear Ni(II) compound. Crystal structure analysis and DFT calculations reveal that the non-covalent cooperative π-stacking interactions involved in the supramolecular association of the compounds are energetically significant. In vitro antiproliferative activities of the compounds have been investigated with the Dalton’s Lymphoma (DL) malignant cancer cell line using MTT cell viability and apoptosis assays. Both the compounds exhibit significant concentration dependent cell cytotoxicity and apoptotic cell death in DL cancer cells, with nominal effects for normal healthy PBMC cells. A decrease in the MMP (mitochondrial membrane potential) and a rapid increase of the ROS (reactive oxygen species) levels in DL cells corroborate the apoptotic cell death induced by the compounds. To support the observed wet lab cytotoxicity in DL cancer cells, we have also carried out in silico molecular docking studies of the compounds with the active sites of antiapoptotic BCL family proteins. Both the Cu(II) and Ni(II) compounds exhibit significant interaction modes with the BCL family cancer target proteins. Pharmacophore features of the structures of the compounds have been identified to establish a structure activity relationship (SAR).