Evaluation of the anticancer activities with various ligand substituents in Co(/)-picolyl phenolate derivatives: synthesis, characterization, DFT, DNA cleavage, and molecular docking studies

• Published in: Dalton transactions : an international journal of inorganic chemistry 2022-02, Vol.51 (6), p.2346-2363
• Main Authors: Jana, Abhimanyu, Aher, Abhishek, Brandao, Paula, Bera, Pradip, Sharda, Saphy, Phadikar, Ujjwal, Manna, Sunil Kumar, Mahapatra, Ajit Kumar, Bera, Pulakesh
• Format: Article
• Language: English
• Subjects: Amines; Anticancer properties; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Benzaldehyde; Cancer; Cell death; Cell Line, Tumor; Cell Proliferation - drug effects; Chelation; Chemical synthesis; Cleavage; Cobalt - chemistry; Cobalt - pharmacology; Cobalt compounds; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Coordination compounds; Crystallography; Density Functional Theory; DNA - chemistry; DNA - metabolism; DNA Cleavage - drug effects; Drug Screening Assays, Antitumor; Humans; Hydrogen peroxide; Kinases; Ligands; Molecular docking; Molecular Docking Simulation; Molecular Structure; NMR; Nuclear magnetic resonance; Oxidation; Singlet oxygen; Structure-Activity Relationship; Toxicity
• ISSN: 1477-9226; 1477-9234; 1477-9234
• DOI: 10.1039/d1dt02825a

The reactions between 2-(pyridine-2-ylmethoxy)-benzaldehyde ( L ) and various primary amines furnish tridentate ( L1 to L3 ) and tetradentate ( L4 ) chelating ligands. The choice of different primary amines in the condensation reaction incorporates the chiral carbon atom in L2 and L3 . A series of mononuclear cobalt( ii ) complexes, [Co II ( L1 )(Cl) 2 ] ( 1 ), [Co II ( L2 )(Cl) 2 ]·CH 3 CN ( 2 ), [Co II ( L3 )(Cl) 2 ] ( 3 ), and [Co III ( L4 )(N 3 ) 2 ] ( 4 ) are synthesized in the pure crystalline state from the resulting solution of cobalt( ii ) chloride and/or azide and respective ligand. The new ligands and cobalt complexes are characterized using spectral (UV-Vis, 1 H-NMR, IR, and HRMS), cyclovoltammetric, and DFT studies. The structure of L1 , L2 , and all four cobalt complexes are determined by single X-ray crystallography. Cytotoxic activity of the compounds is evaluated using three different tissues of origin e.g. , U-937 (histiocytic lymphoma), HEK293T (embryonic kidney), and A549 (lung carcinoma). The cobalt complexes are more active than the corresponding ligands against U-937 and HEK293T. The MTT assay demonstrates that the cobalt compounds are more effective anticancer agents against U-937 cancer cells than HEK293T and A549. The toxicity order, 1 (7.2 ± 0.3 μM) > 3 (11.4 ± 0.6 μM) > 2 (12 ± 0.1 μM) > 4 (29 ± 1 μM) is observed against U-937 cancer cells. All the compounds induce cell death through an apoptosis mechanism and all are ineffective against PBMCs. The mechanism of activity against U937 cancer cells involves caspase-3 activation and two different mitogen-activated protein kinases attesting the programmed cell death. Among the compounds, complexes 1 , 2 , and 3 show DNA cleavage activity both in oxidizing (H 2 O 2 ) and reducing (GSH) environments. The mechanistic study reveals that singlet oxygen ( 1 O 2 ) is the major species involved in DNA cleavage. The absolute chemical hardness values of the ligands and 4 are relatively higher than 1 , 2 , and 3 , which tacitly support the DNA cleavage experiment. The docking result indicates that the compounds under investigation strongly interact with DNA base pairs through a variety of interactions which attests successfully to the experimental results. A structure-activity relationship has been drawn to correlate the variation of antitumor activity with ligand conformations. Four mononuclear cobalt( ii / iii ) complexes have been synthesized and structurally characterized using four differe