Copper(II) Complexes with Highly Water-Soluble L- and D-Proline Thiosemicarbazone Conjugates as Potential Inhibitors of Topoisomerase IIalfa

Bacher, Felix and Enyedy, Éva Anna and Nagy, Nóra Veronika and Rockenbauer, Antal and Bognár, Gabriella M. and Trondl, Robert and Novak, Maria S and Kiss, Tamás and Arion, Vladimir B. (2013) Copper(II) Complexes with Highly Water-Soluble L- and D-Proline Thiosemicarbazone Conjugates as Potential Inhibitors of Topoisomerase IIalfa. INORGANIC CHEMISTRY, 52. pp. 8895-8908. ISSN 0020-1669

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Abstract

Two proline-thiosemicarbazone bioconjugates with excellent aqueous solubility, namely 3-methyl-(S)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone (L-Pro-FTSC or (S)-H2L) and 3-methyl-(R)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone (D-Pro-FTSC or (R)-H2L) have been synthesized and characterized by elemental analysis, one- and two-dimensional 1H and 13C NMR spectroscopy and ESI mass spectrometry. The complexation behavior of L-Pro-FTSC with copper(II) in aqueous solution and in 30% (w/w) dimethyl sulfoxide/water mixture has been studied via pH-potentiometry, UV−vis spectrophotometry, EPR, 1H NMR spectroscopy and spectrofluorometry. By the reaction of copper(II) acetate with (S)-H2L and (R)-H2L in water the complexes [Cu(S,R)-L] and [Cu(R,S)-L] have been synthesized and comprehensively characterized. An X-ray diffraction study of [Cu(S,R)-L] showed the formation of a square-pyramidal complex with the bioconjugate acting as a pentadentate ligand. Both copper(II) complexes displayed antiproliferative activity in CH1 ovarian carcinoma cells and inhibited the Topoisomerase IIα activity in a DNA plasmid relaxation assay.

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