Phenolate-thiazole based reversible "turn-on" chemosensor for the selective detection of carbonate anion: X-ray crystallography, DFT/TDFT, and cell study.

A new phenolate-thiazole derivative (L) has been synthesized and structurally characterized.The chemo-sensing activity of L is detected by the naked eye for the aqueous carbonate anion in the pH range of 4 to 8. The selective 'turn-on' fluorescence occurs through the formation of a stable intermediate L∙CO32-(1) following the PET mechanism. The limit of detection (LOD) is found 0.18 µM based on the absorbance-based assay.The quinonoid form of bromophenol unit binds strongly with CO32- through thiazole nitrogen and hydrazinic nitrogen. Further, the selective holding of CO32- anion over other planar tetranuclear anions (e.g., SO32-, NO3-) happens with several intra and intermolecular hydrogen bonds as envisaged by the DFT/TDFT study. The formation mechanism of L∙CO32- is proposed based on experimental and theoretical studies. The biological experiments (MTT and cell imaging)reveal the non-cytotoxicity nature of L and the biocompatible uptake of L mostly in the cytoplasm at physiological pH.

Instigating the In Vitro Anticancer Activity of New Pyridine-Thiazole-Based Co(III), Mn(II), and Ni(II) Complexes: Synthesis, Structure, DFT, Docking, and MD Simulation Studies.

The perchlorate salt of (4-(4-methoxy phenyl)-2-(2-(1-pyridine-2-yl)ethylidene)hydrazinyl)thiazole (PytH·ClO4) and its metal perchlorate derivatives, namely, [Co(Pyt)2]ClO4 (1), [Mn(PytH)2](ClO4)2 (2), and [Ni(PytH)2](ClO4)2 (3), have been synthesized and characterized through single X-ray crystallography and spectroscopic methods. The ligand crystallizes in a space group P21/n in a nearly planar structure. The overall geometry of the complex salts is described as a distorted octahedron with a MN6 chromophore. The ligand (PytH·ClO4) behaves as a neutral N,N,N-tridentate donor toward the "soft" Mn(II) and Ni(II) centers, whereas the deprotonated ligand stabilizes the "hard" Co(III) center. The DNA binding constant (Kb) values of PytH·ClO4, 1, 2, and 3 are determined using the UV-vis spectroscopic method, and the Kb values are 9.29 × 105, 7.11 × 105, 8.71 × 105, and 7.82 × 105 mol-1, respectively, indicating the intercalative mode of interactions with CT-DNA. All the derivatives show effective antiproliferative activity against U-937 human monocytic tumor cells with IC50 values 4.374 ± 0.02, 5.583 ± 0.12, 0.3976 ± 0.05, and 11.63 ± 0.01 µM for PytH·ClO4, 1, 2, and 3, respectively. The best apoptosis mode of cell death is shown by 2 followed by PytH·ClO4 and 1 at an equivalent concentration of IC50 values. The combined molecular docking and dynamics simulation study evaluates the binding energies of anticancer agents, providing groove binding property with DNA. The 20 ns molecular dynamics simulation study reveals the maximum DNA binding stability of 2 corroborating the experimental results. The new class of metal derivatives of pyridine-thiazole can be used for advanced cancer therapeutics.

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

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, [CoII(L1)(Cl)2] (1), [CoII(L2)(Cl)2]·CH3CN (2), [CoII(L3)(Cl)2] (3), and [CoIII(L4)(N3)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, 1H-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 (H2O2) and reducing (GSH) environments. The mechanistic study reveals that singlet oxygen (1O2) 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.

In silico Insights on IL-6: A Potential Target for Multicentric Castleman Disease.

BACKGROUND: Multicentric Castleman Disease (MCD) is a confrontational lymphoproliferative disorder described by symptoms such as lymph node proliferation, unwarranted secretion of inflammatory cytokines, hyperactive immune system, and in severe cases, multiple organ dysfunction. Interleukin-6 (IL-6) is a pleiotropic cytokine which is involved in a large range of physiological processes in our body such as pro-inflammation, anti-inflammation, differentiation of T-cells and is reported to be a key pathological factor in MCD. In the case of MCD, it was observed that IL-6 is overproduced from T-cells and macrophages which disturb Hepcidin, a vital regulator of iron trafficking in macrophage. The present study endeavour to expound the inhibitor which binds to IL-6 protein receptor with high affinity. METHODS: MolegroVirtual Docker software was employed to find the best-established drug from the list of selected inhibitors of IL-6. This compound was subjected to virtual screening against PubChem database to get inhibitors with a very similar structure. These inhibitors were docked to obtain a compound binding with high affinity to the target protein. The established compound and the virtual screened compound were subjected to relative analysis of interactivity energy variables and ADMET profile studies. RESULTS: Among all the selected inhibitors, the virtual screened compound PubChem CID: 101119084 is seen to possess the highest affinity with the target protein. Comparative studies and ADMET analysis further implicate this compound as a better inhibitor of the IL-6 protein. CONCLUSION: Hence, this compound recognized in the study possesses high potential as an IL-6 inhibitor which might assist in the treatment of Multicentric Castleman Disease and should be examined for its efficiency by in vivo studies.