Evaluation of anticancer activities with various ligand substituents in Co(II/III)-picolyl phenolate derivatives: synthesis, characterization, DFT, DNA cleavage and molecular docking studies
Larry A. Watts
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This article was originally published here
Dalton Trans. 2022 Jan 19. doi: 10.1039/d1dt02825a. Online ahead of print.
ABSTRACT
Reactions between 2-(pyridin-2-ylmethoxy)-benzaldehyde (L) and various primary amines yield tridentate (L1 to L3) and tetradentate (L4) chelating ligands. The choice of different primary amines in the condensation reaction incorporates the chiral carbon atom into L2 and L3. A series of mononuclear cobalt(II) complexes, [CoII(L1)(Cl)2] (1), [CoII(L2)(Cl)2]CH3NC (2), [CoII(L3)(Cl)2] (3), and [CoIII(L4)(N3)2] (4) are synthesized in pure crystalline form from the resulting solution of cobalt(II) chloride and/or azide and the respective ligand. New cobalt ligands and complexes are characterized by spectrum (UV-Vis, 1H-NMR, IR and HRMS), cyclovoltammetric and DFT studies. The structure of L1, L2 and the four cobalt complexes is determined by simple X-ray crystallography. The cytotoxic activity of the compounds is evaluated using three different tissues of origin for example, U-937 (histiocytic lymphoma), HEK293T (embryonic kidney) and A549 (pulmonary carcinoma). Cobalt complexes are more active than the corresponding ligands against U-937 and HEK293T. The MTT assay demonstrates that cobalt compounds are more effective anti-cancer agents against U-937 cancer cells than HEK293T and A549. The order of toxicity, 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 compounds induce cell death through an apoptotic mechanism and all are ineffective against PBMCs. The mechanism of activity against U937 cancer cells involves the activation of caspase-3 and two different mitogen-activated protein kinases attesting to programmed cell death. Among the compounds, complexes 1, 2 and 3 show DNA-cleaving activity both in oxidizing (H2O2) and reducers (GSH). The mechanistic study reveals that singlet oxygen (1O2) is the main species involved in DNA cleavage. The absolute values of chemical hardness of ligands and 4 are relatively higher than 1, 2 and 3, which tacitly supports the DNA cleavage experiment. The docking result indicates that the compounds under study strongly interact with DNA base pairs through a variety of interactions that attest to successful experimental results. A structure-activity relationship was established to correlate variation in antitumor activity with ligand conformations.
PMID:35043134 | DO I:10.1039/d1dt02825a
