Anupa A. Kumbhar

The catecholase-like activity of a mononuclear Cu( ii ) complex, CuCIP, was investigated in aqueous medium using di- tert -butyl-catechol (DTBC) as a substrate, and the mechanism was established by UV-visible spectroscopy, EPR, and cyclic voltammetry.

A series of new 1-(2-pyridyl) piperazinyl and isatin based thiosemicarbazones and respective copper(II) complexes (1-7) have been synthesized and characterized by ESI-HRMS, 1H NMR, 13C NMR, UV-Vis, FTIR, single crystal X-ray (SC-XRD), PXRD, EPR, TGA, and elemental analysis. The copper(II) complexes are mononuclear with distorted square planar geometry. B3LYP/ LANL2DZ DFT calculations indicated that complexation with copper decreased the HOMO-LUMO energy gap of the ligands from 2.912 – 2.993 eV to 2.014 – 2.068 eV conforming an increase in chemical reactivity. Molecular docking study confirms the strong binding affinities of compound 1 and 6 (binding energy, -7.9 kcal/mol and -8.6 kcal/mol, respectively) toward the EGFR protein, stabilized by a network of hydrogen and hydrophobic interactions with key active site residues. This study strongly supports in vitro data observed against cancer cells (MCF-7, A431) and non-cancer cell (PNT2) in terms of cell viability at 10 μM/mL concentration. The compounds performed remarkable cancer cell growth inhibition (52-32% in MCF-7 & 57-18% in A431). Coordination of ligands with copper(II) ion resulted in increase of their anticancer potency mostly towards MCF-7 cells. The toxicity of ligands toward PNT2 has been found to decrease on coordination to Cu2+ ion. Compounds 1 and 6 revealed the significant anticancer potency with the cell growth inhibition of 57% and 52% in A431 and MCF-7 cells respectively. These compounds act as potent anticancer agents and need mechanistic study to be used as non-platinum anticancer drug.

Isatin-4-(2,6-dimethyl morpholinyl)-3-thiosemicarbazone (Istdmpln), and its copper(II) thiosemicarbazone (Cu-istdmpln) were prepared and analysed using CHNS analysis, mass spectrometry, NMR, UV-Vis, FTIR, EPR spectroscopy, and thermogravimetric analysis (TGA). Copper(II) thiosemicarbazone exhibited mononuclear square planar geometry with ONS linkage of thiosemicarbazone and a chloride ion. The absence of chemical shift (δ) at 4 ppm confirmed the formation of ligand in thione form. The shift of IR band corresponding to N–N toward higher energy and that of C=O and C=N toward lower energy confirmed the chelation of thiosemicarbazone to copper(II) ion. The Cu(II) complex exhibited significantly higher cell growth inhibition property than its ligand against both cancer cell lines (IC50; 13.01 µM, HCT116 and IC50; 31.19 µM, MDA-MB-231). The free ligand in aforementioned cell lines exhibited anticancer activity with the higher micromolar concentration (IC50; 34.64 µM, HCT116 and IC50; 43.99 µM, MDA-MB-231). The IC50 bar diagram showed that the Cu(II) complex is about 3 and 1.5 times more potent than the free ligand toward HCT116 and MDA-MB-231 cancer cells, respectively. Additionally, both ligand and copper(II) complex showed low toxicity toward normal embryonic kidney cell (HEK293) with IC50 15.39-16.72 µM. Molecular docking analysis showed that both Istdmpln and Cu-istdmpln are effective in inhibiting the EGFR protein with the significant binding energy (kcal/mol) of -8.1 and -8.9, respectively. The remarkable result of anticancer potency on coordination of ligand to copper(II) ion encourages for mechanistic and in vivo studies of the synthesized compounds.

A new colorimetric and fluorescence turn‐on chemodosimeter for selective detection of GSH over Cys and Hcy with 34‐fold enhancement in emission intensity is reported. Probe 1 exhibited ultra‐sensitivity toward GSH with 0.125 nM detection limit and successfully displayed GSH detection in MCF‐7 live cells. The mechanism of sensing is established by density functional theoretical calculations.

In the last few decades, natural products from plants have developed immense importance in human health due to their therapeutic multi-functionality. They have also been reported to enhance human gut health, which is another important factor in overall human health. Diabetes Mellitus Type 2 (DM 2) is now a global concern with 6.28% of the world’s population affected by it. Many hypoglycemic drugs currently available in the market are either directly or indirectly based on a number of plant secondary metabolites. In the current study, we aimed to find out the hypoglycemic secondary metabolites from a leaf methanolic extract of Argyreia nervosa (Burm. f.) Bojer (Family: Convolvulaceae). In the in vitro experiment, this extract showed good inhibitory activity against Porcine Pancreatic Alpha-amylase (PPA) with IC₅₀ value of 1.1 mg/mL. The presence of Quercetin and Ursolic acid was identified in the leaf methanolic extract using HPTLC, HPLC, and MS analysis. The calculated IC₅₀ values against PPA, for standard Quercetin and Ursolic acid, were 16.5 µg/mL and 13.2 µg/mL, respectively. The in silico studies used both of these compounds as ligands against PPA (PDB ID: 1OSE) in AutoDock 4.2.6. Significant binding energies of −9.89 kcal/mol and −8.96 kcal/mol were seen for Quercetin and Ursolic acid, respectively, while Acarbose (the drug used as the positive control) had a binding energy of −12.48 kcal/mol. Both Quercetin and Ursolic acid strongly interacted with the pivotal amino acid residues such asGlu233, Asp197, and Asp300, which are present at the active site of PPA, thus upholding our in vitro experimental results. Both the compounds have exhibited beneficial effects on human gut health in DM 2 and related complications. The docking results of them with a few intestinal markers that are significant in gut health will also be discussed.

A series of N(4) thiomorpholinyl isatin/5-haloisatin thiosemicarbazones and their copper(II) complexes (1-8) were prepared and characterized by elemental analysis, NMR, IR, ESI-HRMS, UV-Visible, EPR, TGA powder and single crystal X-ray diffraction studies. The copper(II) complexes possess distorted square planar geometry. The single crystal X-ray study of compounds (1-3) confirmed their existence in thione tautomeric form. Thein vitro aniproliferative study of the compounds against cancer cells MCF-7, A431 and normal cell PNT2 showed significant antiproliferative activity for both ligands and complexes. The anticancer activity of the compound 4 was found higher (0.61±0.13) than corresponding complex (0.73±1.18) toward MCF-7 cell line. Although, the compound 4 did not show good effect in A431 (1.19±0.03) cell line, it was least toxic in PNT2 cell line. The compound 3 showed higher anti-proliferative activity in A431 (0.47±0.28) cell line. The compound 1 exhibited lowest anti-proliferative activity against MCF-7 (0.94±0.07) cell line. Overall, out of all the studied compounds, compound 4 and its complex showed the best anti-proliferative activity for MCF-7 cell line. Also, they were less-toxic to normal cells so they could be further studied at different level of anticancer tests to be used as high efficacy non-platinum anticancer drugs.

Two new Cu(II) complexes, of the type CuL1 and CuL2 , of asymmetric bis(thiosemicarbazone) ligands were synthesized where L1 =(E)‐2‐((E)‐3‐(2‐((E)‐2‐(naphthalen‐1‐yl methylene) hydrazine carbonothioyl) hydrazono) butan‐2‐ylidene) hydrazine carbothioamide and L2 =(E)‐N‐methyl‐2‐(3‐oxobutan‐2‐ylidene) hydrazine carbothioamide and characterized by elemental analysis, HRMS, IR, EPR and cyclic voltammetry. The complexes undergo reversible one‐electron reduction at E _1/2 =∼−0.52 V vs Ag/AgCl. Interaction of CuL1 and CuL2 with human serum albumin monitored by fluorescence spectroscopy revealed static quenching with binding constants of the order of 10 ⁵ M ⁻¹ . Their cellular uptake and cytotoxicity were studied on MCF‐7 and NIH‐3T3 cells. The results indicate that CuL1 is more cytotoxic owing to its cellular permeability.