Abstract
Thiosemicarbazones continue to attract the interest of researchers as potential anticancer drugs. For example, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, or triapine, is the most well-known representative of this class of compounds that has entered multiple phase I and II clinical trials. Two new triapine derivatives HL1 and HL2 were prepared by condensation reactions of 2-pyridinamidrazone and S-methylisothiosemicarbazidium chloride with 3-N-(tert-butyloxycarbonyl) amino-pyridine-2-carboxaldehyde, followed by a Boc-deprotection procedure. Subsequent reaction of HL1 and HL2 with CuCl2·2H2O in 1:1 molar ratio in methanol produced the complexes [CuII(HL1)Cl2]·H2O (1·H2O) and [CuII(HL2)Cl2] (2). The reaction of HL2 with Fe(NO3)3∙9H2O in 2:1 molar ratio in the presence of triethylamine afforded the complex [FeIII(L2)2]NO3∙0.75H2O (3∙0.75H2O), in which the isothiosemicarbazone acts as a tridentate monoanionic ligand. The crystal structures of HL1, HL2 and metal complexes 1 and 2 were determined by single crystal X-ray diffraction. The UV-Vis and EPR spectroelectrochemical measurements revealed that complexes 1 and 2 underwent irreversible reduction of Cu(II) with subsequent ligand release, while 3 showed an almost reversible electrochemical reduction in dimethyl sulfoxide (DMSO). Aqueous solution behaviour of HL1 and 1, as well as of HL2 and its complex 2, was monitored as well. Complexes 1−3 were tested against ovarian carcinoma cells, as well as noncancerous embryonic kidney cells, in comparison to respective free ligands, triapine and cisplatin. While the free ligands HL1 and HL2 were devoid of antiproliferative activity, their respective metal complexes showed remarkable antiproliferative activity in a micromolar concentration range. The activity was not related to the inhibition of ribonucleotide reductase (RNR) R2 protein, but rather to cancer cell homeostasis disturbance—leading to the disruption of cancer cell signalling.
Highlights
Introduction αN-Heterocyclic thiosemicarbazones (TSCs) attract considerable attention since their remarkable antiproliferative properties have been discovered [1]
The most promising representative of this group of compounds is 3-aminopyridine-2-carboxaldehyde thiosemicarbazone or triapine (3-AP), which has already entered more than 30 phase I and II clinical trials [2,3,4]. 3-AP was tested in various combination regimens and was shown to enhance the activity of other anticancer drugs, such as cisplatin [2,5], gemcitabine [6], doxorubicin [7], irinotecan [4]
IR spectra were reported on a Bucker Vertex 70 Fourier transform IR spectrometer (4000–400 cm−1) using the ATR technique. 1D (1H, 13C) and 2D (1H-1H COSY, 1H-1H TOCSY, 1H-1H NOESY, 1H-13C HSQC, 1H-13C HMBC, 1H-15N HSQC, 1H-15N HMBC) NMR spectra were measured on a Bruker AV NEO 500 or AV III 600 spectrometers (Bruker BioSpin GmbH, Rheinstetten, Germany) in dimethyl sulfoxide (DMSO)-d6 at 25 ◦C at NMR spectroscopy Centre of the Faculty of Chemistry of the University of Vienna
Summary
Elemental analyses were carried out in a Carlo-Erba microanalyser at the Microanalytical Laboratory of the University of Vienna. Electrospray ionisation mass spectrometry (ESI MS) was carried out with amaZon speed ETD Bruker instrument (Bruker Daltonik GmbH, Bremen, Germany, m/z range 0–900, ion positive/negative mode, 180 ◦C, heating gas N2 (5 L/min), Capillary 4500 V, End Plate Offset 500 V). UV–Vis spectra were measured on Perkin Elmer UV/Vis spectrophotometer Lambda 35. 1D (1H, 13C) and 2D (1H-1H COSY, 1H-1H TOCSY, 1H-1H NOESY, 1H-13C HSQC, 1H-13C HMBC, 1H-15N HSQC, 1H-15N HMBC) NMR spectra were measured on a Bruker AV NEO 500 or AV III 600 spectrometers (Bruker BioSpin GmbH, Rheinstetten, Germany) in DMSO-d6 at 25 ◦C at NMR spectroscopy Centre of the Faculty of Chemistry of the University of Vienna IR spectra were reported on a Bucker Vertex 70 Fourier transform IR spectrometer (4000–400 cm−1) using the ATR technique. 1D (1H, 13C) and 2D (1H-1H COSY, 1H-1H TOCSY, 1H-1H NOESY, 1H-13C HSQC, 1H-13C HMBC, 1H-15N HSQC, 1H-15N HMBC) NMR spectra were measured on a Bruker AV NEO 500 or AV III 600 spectrometers (Bruker BioSpin GmbH, Rheinstetten, Germany) in DMSO-d6 at 25 ◦C at NMR spectroscopy Centre of the Faculty of Chemistry of the University of Vienna
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
