Copper(II) Complexes with Highly Water-Soluble l- and d‑Proline–Thiosemicarbazone Conjugates as Potential Inhibitors of Topoisomerase IIα

• Published in: Inorganic chemistry Vol. 52; no. 15; pp. 8895 - 8908
• Main Authors: Bacher, Felix, Enyedy, Éva A, Nagy, Nóra V, Rockenbauer, Antal, Bognár, Gabriella M, Trondl, Robert, Novak, Maria S, Klapproth, Erik, Kiss, Tamás, Arion, Vladimir B
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 05.08.2013
• Subjects: Antigens, Neoplasm; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Copper - chemistry; DNA Topoisomerases, Type II; DNA-Binding Proteins - antagonists & inhibitors; Humans; Models, Molecular; Molecular Conformation; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - metabolism; Organometallic Compounds - pharmacology; Serum Albumin - metabolism; Solubility; Spectrum Analysis; Stereoisomerism; Thiosemicarbazones - chemistry; Topoisomerase II Inhibitors - chemical synthesis; Topoisomerase II Inhibitors - chemistry; Topoisomerase II Inhibitors - metabolism; Topoisomerase II Inhibitors - pharmacology; Water - chemistry
• ISSN: 0020-1669; 1520-510X
• DOI: 10.1021/ic401079w

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 electrospray ionization mass spectrometry. The complexation behavior of l-Pro-FTSC with copper(II) in an aqueous solution and in a 30% (w/w) dimethyl sulfoxide/water mixture has been studied via pH potentiometry, UV–vis spectrophotometry, electron paramagnetic resonance, 1H NMR spectroscopy, and spectrofluorimetry. 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 Topoisomerase IIα activity in a DNA plasmid relaxation assay.