Abstract
Solution chemical properties of two bidentate pyrazolyl thiosemicarbazones 2-((3-methyl-1-phenyl-1H-pyrazol-4-yl)methylene)hydrazinecarbothioamide (Me-pyrTSC), 2-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)hydrazinecarbothioamide (Ph-pyrTSC), stability of their Cu(II) and Ru(η6-p-cymene) complexes were characterized in aqueous solution (with 30% DMSO) by the combined use of UV–visible spectrophotometry, 1H NMR spectroscopy and electrospray ionization mass spectrometry in addition to their solid phase isolation. The solid phase structures of Me-pyrTSC∙H2O, [Ru(η6-p-cymene)(Me-pyrTSC)Cl]Cl and [Cu(Ph-pyrTSCH−1)2] were determined by single crystal X-ray diffraction. High stability mononuclear Ru(η6-p-cymene) complexes with (N,S) coordination mode are formed in the acidic pH range, and increasing the pH the predominating dinuclear [(Ru(η6-p-cymene))2(L)2]2+ complex with μ2-bridging sulphur donor atoms is formed (where L− is the deprotonated thiosemicarbazone). [CuL]+ and [CuL2] complexes show much higher stability compared to that of complexes of the reference compound benzaldehyde thiosemicarbazone. [CuL2] complexes predominate at neutral pH. Me-pyrTSC and Ph-pyrTSC exhibited moderate cytotoxicity against human colonic adenocarcinoma cell lines (IC50 = 33–76 μM), while their complexation with Ru(η6-p-cymene) (IC50 = 11–24 μM) and especially Cu(II) (IC50 = 3–6 μM) resulted in higher cytotoxicity. Cu(II) complexes of the tested thiosemicarbazones were also cytotoxic in three breast cancer and in a hepatocellular carcinoma cell line. No reactive oxygen species production was detected and the relatively high catalase activity of SUM159 breast cancer cells was decreased upon addition of the ligands and the complexes. In the latter cell line the tested compounds interfered with the glutathione synthesis as they decreased the concentration of this cellular reductant.
Highlights
Thiosemicarbazones (TSCs) are versatile compounds and known for their wide pharmacological activity including anticancer properties [1,2]
Subsequent cyclization and simultaneous formylation with the Vilsmeier-Haack reagent (POCl3/DMF) afforded 4-formyl-pyrazoles (3a and 3b) [46], which were converted to thiosemicarbazones (MepyrTSC and Ph-pyrTSC) and a semicarbazone (Ph-pyrSC), respectively, in the presence of acetic acid (Me-pyrTSC and Ph-pyrTSC) or sodium acetate (Ph-pyrSC) [27] in ethanol under MW irradiation. 1H and 13C NMR spectra were in agreement with the expected structures of the intermediates and the final products and the 1H and 13C resonances published previously [27,46,47,48,49,50]
No significant changes were seen upon addition of Cu (II) to the ligands. These results suggest that the tested compounds may cause changes in antioxidant transcription factor Nrf2, which is responsible for transcription of enzymes needed for GSH synthesis [59] independently of ROS production
Summary
Thiosemicarbazones (TSCs) are versatile compounds and known for their wide pharmacological activity including anticancer properties [1,2]. Two new promising TSCs, namely N′(6,7-dihydroquinolin-8(5H)-ylidene)-4-(pyridin-2-yl)piperazine-1-carbothiohydrazide (COTI-2, an orally available third generation TSC) and di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) entered human clinical studies in the last years [5,6]. These compounds belong to the family of α-N-pyridyl TSCs, are considered as tridentate ligands with a typical (Npyridyl,N,S) coordination mode with strong affinity towards various metal ions including Fe (II/III) and Cu(II) [7]. The anticancer properties of Triapine are connected to the inhibition of the iron-containing ribonucleotide reductase enzyme and the formation of redox-active iron complexes in the cells is suggested to be a crucial step of the mechanism of action [8]. Till numerous Cu(II) complexes of TSCs were developed for anticancer activity [15,16] and generation of reactive oxygen
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