Thiosemicarbazone(s)-anchored water soluble mono- and bimetallic Cu(<scp>ii</scp>) complexes: enzyme-like activities, biomolecular interactions, anticancer property and real-time live cytotoxicity
Nithya Balakrishnan, Jebiti Haribabu, Anantha Krishnan Dhanabalan, Srividya Swaminathan, Sijia Sun, Dya Fita Dibwe, Nattamai Bhuvanesh, Suresh Awale, Ramasamy Karvembu
Abstract
The reactions of CuCl2·2H2O with chromone thiosemicarbazone ligands containing a -H or -CH3 substituent on terminal N yielded monometallic Cu(ii) complexes [Cu(HL1)Cl2] (1) and [Cu(HL2)Cl2] (2), whereas bimetallic Cu(ii) complexes [Cu(μ-Cl)(HL3)]2Cl2 (3), [Cu(μ-Cl)(HL4)]2Cl2 (4) and [Cu(μ-Cl)(L5)]2 (5) were obtained when a -C2H5, -C6H11 or -C6H5 substituent was present, respectively, in the ligands. The complexes were characterized using elemental analyses, UV-Vis, FT-IR, EPR, mass and TGA studies. The structures of neutral monometallic and dicationic bimetallic complexes were confirmed by single crystal X-ray diffraction, and they exhibited a distorted square pyramidal geometry around Cu(ii) ions. The catecholase-mimicking activity of complexes 1-5 was examined spectrophotometrically, and the results revealed that all the complexes except 5 had the ability to oxidize 3,5-di-tert-butylcatechol (3,5-DTBC) to 3,5-di-tert-butylquinone (3,5-DTBQ) under aerobic conditions with moderate turnover numbers. In order to find the possible complex-substrate intermediates, a mass spectrometry study was carried out for complexes 1-4 in the presence of 3,5-DTBC. The phosphatase-like activity of 1-5 was also investigated using 4-nitrophenylphosphate (4-NPP) as a model substrate. All the complexes exhibited excellent phosphatase activity in DMF-H2O medium. The complexes displayed significant biomolecular interactions and antioxidant potential. Complex 3 showed good interaction with apoptotic CASP3 protein, VEGFR2 and PIM-1 kinase receptors as revealed by a molecular docking study. Complexes (3-5) exhibited promising cytotoxicity against HeLa-cervical cancer cells with IC50 values of 2.24 (3), 2.25 (4) and 3.77 (5) μM, respectively, and showed a two-fold higher activity than cisplatin. The active complex 3 showed complete inhibition of colony formation at 10 μM concentration. In addition, the acridine orange (AO)/ethidium bromide (EB) staining and real-time live cell imaging results confirmed that complex 3 induced cell death in HeLa cells.