Abstract
As ribonucleotide reductase (RNR) plays a crucial role in nucleic acid metabolism, it is an important target for anticancer therapy. The thiosemicarbazone Triapine is an efficient R2 inhibitor, which has entered ∼20 clinical trials. Thiosemicarbazones are supposed to exert their biological effects through effectively binding transition-metal ions. In this study, six iminodiacetate-thiosemicarbazones able to form transition-metal complexes, as well as six dicopper(II) complexes, were synthesized and fully characterized by analytical, spectroscopic techniques (IR, UV-vis; 1H and 13C NMR), electrospray ionization mass spectrometry, and X-ray diffraction. The antiproliferative effects were examined in several human cancer and one noncancerous cell lines. Several of the compounds showed high cytotoxicity and marked selectivity for cancer cells. On the basis of this, and on molecular docking calculations one lead dicopper(II) complex and one thiosemicarbazone were chosen for in vitro analysis as potential R2 inhibitors. Their interaction with R2 and effect on the Fe(III)2-Y· cofactor were characterized by microscale thermophoresis, and two spectroscopic techniques, namely, electron paramagnetic resonance and UV-vis spectroscopy. Our findings suggest that several of the synthesized proligands and copper(II) complexes are effective antiproliferative agents in several cancer cell lines, targeting RNR, which deserve further investigation as potential anticancer drugs.
Highlights
Thiosemicarbazones are well-known for their versatile coordination chemistry,[1] biological activity[2] and theranostic applications.1a,3 3-Amino-2-pyridinecarboxaldehyde thiosemicarbazone, referred to as Triapine, a very efficient inhibitor of ribonucleotide reductase (RNR),[4] has entered a number of clinical trials[5,6,7] and showed promising results in treatment of hematological diseases.[8]
A series of six iminodiacetate-thiosemicarbazone hybrids and six dicopper(II) complexes, the latter resulting from reactions of copper(II) salts with the proligands, have been synthesized and characterized by X-ray diffraction, analytical and spectroscopic techniques
All compounds were assayed for antiproliferative activity in four cancer and one noncancerous cell lines showing moderate to high cytotoxicity often exceeding that of the clinical drug cisplatin
Summary
Thiosemicarbazones are well-known for their versatile coordination chemistry,[1] biological activity[2] and theranostic applications.1a,3 3-Amino-2-pyridinecarboxaldehyde thiosemicarbazone, referred to as Triapine, a very efficient inhibitor of ribonucleotide reductase (RNR),[4] has entered a number of clinical trials[5,6,7] and showed promising results in treatment of hematological diseases.[8]. Note that investigation of thiosemicarbazones as potential anticancer agents in the 1950s followed the studies which demonstrated their antiviral activity.[25,26] L- and D-proline 5-methyl-salicylaldehyde thiosemicarbazones along with their copper(II) complexes were prepared and compared for antiproliferative activity in vitro.[27] The synthesis was further extended by replacing the phenolic moiety by a pyridine functionality,[28] since it was known that N-heterocyclic thiosemicarbazones with potential NNS binding sites for transition metals have increased antiproliferative activity both in vitro and in vivo.[17] Highly water-soluble copper(II) L- and D-proline 2-pyridinecarboxaldehyde thiosemicarbazones were found to act as inhibitors of topoisomerase IIα and display antiproliferative activity in CH1 ovarian carcinoma cells.[29] Thiosemicarbazones exert their biological effects through the ability to effectively bind transition metal ions, in particular, iron(III).[30] remarkable cell-dependent cytotoxicity of dicopper(II) and dizinc(II) complexes with dinucleating ligands based on indolo[3,2-c]quinolines in A549 (nonsmall cell lung carcinoma), CH1 (ovarian carcinoma) and SW480 (colon adenocarcinoma) cell lines has been shown. All copper(II) complexes have been investigated by X-ray crystallography
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