NDLI: Strong effect of copper(II) coordination on antiproliferative activity of thiosemicarbazone–piperazine and thiosemicarbazone

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Chugunova, Anastasia Filipovic, Lana Arion, Vladimir B. Enyedy, Éva A. Dömötör, Orsolya Radulovic, Sinisa Nagy, Nóra V. Bacher, Felix
Description	Author Affiliation: Bacher F ( University of Vienna, Faculty of Chemistry, Institute of Inorganic Chemistry, Währinger Strasse 42, A-1090 Vienna, Austria. vladimir.arion@univie.ac.at.)
Abstract	In this study, 2-formylpyridine thiosemicarbazones and three different heterocyclic pharmacophores were combined to prepare thiosemicarbazone–piperazine mPip-FTSC $(HL^{1})$ and mPip-dm-FTSC $(HL^{2}),$ thiosemicarbazone–morpholine Morph-FTSC $(HL^{3})$ and Morph-dm-FTSC $(HL^{4}),$ thiosemicarbazone–methylpyrrole-2-carboxylate hybrids mPyrr-FTSC $(HL^{5})$ and mPyrr-dm-FTSC $(HL^{6})$ as well as their copper(II) complexes [CuCl(mPipH-FTSC-H)]Cl (1 + H)Cl, [CuCl(mPipH-dm-FTSC-H)]Cl (2 + H)Cl, [CuCl(Morph-FTSC-H)] (3), [CuCl(Morph-dm-FTSC-H)] (4), $[CuCl(mPyrr-FTSC-H)(H_{2}O)]$ (5) and $[CuCl(mPyrr-dm-FTSC-H)(H_{2}O)]$ (6). The substances were characterized by elemental analysis, one- and two-dimensional NMR spectroscopy $(HL^{1}–HL^{6}),$ ESI mass spectrometry, IR and UV–vis spectroscopy and single crystal X-ray diffraction (1–5). All compounds were prepared in an effort to generate potential antitumor agents with an improved therapeutic index. In addition, the effect of structural alterations with organic hybrids on aqueous solubility and copper(II) coordination ability was investigated. Complexation of ligands $HL^{2}$ and $HL^{4}$ with copper(II) was studied in aqueous solution by pH-potentiometry, UV–vis spectrophotometry and EPR spectroscopy. Proton dissociation processes of $HL^{2}$ and $HL^{4}$ were also characterized in detail and microscopic constants for the Z/E isomers were determined. While the hybrids $HL^{5},$ $HL^{6}$ and their copper(II) complexes 5 and 6 proved to be insoluble in aqueous solution, precluding antiproliferative activity studies, the thiosemicarbazone–piperazine and thiosemicarbazone–morpholine hybrids $HL^{1}–HL^{4},$ as well as copper(II) complexes 1–4 were soluble in water enabling cytotoxicity assays. Interestingly, the metal-free hybrids showed very low or even a lack of cytotoxicity $(IC_{50}$ values > 300 μM) in two human cancer cell lines HeLa (cervical carcinoma) and A549 (alveolar basal adenocarcinoma), whereas their copper(II) complexes were cytotoxic showing $IC_{50}$ values from 25.5 to 65.1 μM and 42.8 to 208.0 μM, respectively in the same human cancer cell lines after 48 h of incubation. However, the most sensitive for $HL^{4}$ and complexes 1–4 proved to be the human cancer cell line LS174 (colon carcinoma) as indicated by the calculated $IC_{50}$ values varying from 13.1 to 17.5 μM.
ISSN	14779226
Issue Number	19
Volume Number	44
e-ISSN	13645447
Journal	Dalton Trans.
Language	English
Publisher	Royal Society of Chemistry
Publisher Date	2015-05-21
Publisher Place	Great Britain (UK)
Access Restriction	Subscribed
Subject Keyword	Antineoplastic Agents Pharmacology Copper Morpholines Organometallic Compounds Piperazines Thiosemicarbazones Chemical Synthesis Chemistry Cell Line, Tumor Cell Proliferation Drug Effects Crystallography, X-Ray Dose-Response Relationship, Drug Drug Screening Assays, Antitumor HeLa Cells Humans Models, Molecular Molecular Structure Structure-Activity Relationship Journal Article Research Support, Non-U.S. Gov't
Content Type	Text
Resource Type	Article
Subject	Inorganic Chemistry

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