Abstract
A series of thiosemicarbazone-coumarin hybrids (HL1-HL3 and H2L4) has been synthesised in 12 steps and used for the preparation of mono- and dinuclear copper(II) complexes, namely Cu(HL1)Cl2 (1), Cu(HL2)Cl2 (2), Cu(HL3)Cl2 (3) and Cu2(H2L4)Cl4 (4), isolated in hydrated or solvated forms. Both the organic hybrids and their copper(II) and dicopper(II) complexes were comprehensively characterised by analytical and spectroscopic techniques, i.e., elemental analysis, ESI mass spectrometry, 1D and 2D NMR, IR and UV–vis spectroscopies, cyclic voltammetry (CV) and spectroelectrochemistry (SEC). Re-crystallisation of 1 from methanol afforded single crystals of copper(II) complex with monoanionic ligand Cu(L1)Cl, which could be studied by single crystal X-ray diffraction (SC-XRD). The prepared copper(II) complexes and their metal-free ligands revealed antiproliferative activity against highly resistant cancer cell lines, including triple negative breast cancer cells MDA-MB-231, sensitive COLO-205 and multidrug resistant COLO-320 colorectal adenocarcinoma cell lines, as well as in healthy human lung fibroblasts MRC-5 and compared to those for triapine and doxorubicin. In addition, their ability to reduce the tyrosyl radical in mouse R2 protein of ribonucleotide reductase has been ascertained by EPR spectroscopy and the results were compared with those for triapine.
Highlights
Synthetic nucleoside analogues and Schiff bases are used as suitable models for investigation of nucleic acids and as chelating agents for application in different fields of research [1,2]
COLO-205 and COLO-320 cells were cultured in RPMI-1640 medium containing 10% foetal bovine serum, MRC-5 cells were cultured in EMEM medium containing 10% foetal bovine serum
The concentration of the tyrosyl radical in mouse R2 ribonucleotide reductase protein was determined by double integration of electron paramagnetic resonance (EPR) spectra recorded at non-saturating microwave power levels (3.2 mW) and compared with the copper standard [55] mR2 protein was expressed, purified, and iron-reconstituted as described previously [56] and passed through a 5 mL HiTrap desalting column (GE Healthcare) to remove excess iron
Summary
Synthetic nucleoside analogues and Schiff bases are used as suitable models for investigation of nucleic acids and as chelating agents for application in different fields of research [1,2]. A biologically active coumarin (or 2H-chromen-2-one) fragment (Chart 1, right) was selected to be incorporated, due to its well-documented wide spectrum of activities, including antibacterial, antifungal, neuroprotective, antiamoebic, anti-inflammatory, and cytotoxic properties [27,28,29,30,31,32,33,34,35,36,37,38] Another biologically active piperazine fragment was included, since heteroaromatic ring systems are considered highly impactful design elements for the optimisation of key pharmacological parameters [23,39]. Complexes 1 and 3 (see Chart 2) was investigated, and compared with that of triapine
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