SYNTHESIS, CHARACTERIZATION, EGFR DOCKING, AND ANTICANCER EVALUATION OF ISATIN DIMETHYL MORPHOLINYL THIOSEMICARBAZONE AND ITS COPPER(II) COMPLEX
Keywords:
Breast cancer, Colorectal cancer, Cu(II) complex, Isatin, ThiosemicarbazoneAbstract
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.
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