title: Copper(II) complexes with highly water-soluble L- and D-proline-thiosemicarbazone conjugates as potential inhibitors of Topoisomerase IIα.
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 (1)H and (13)C 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, (1)H 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.
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Währinger Strasse 42, A-1090 Vienna, Austria.
authors.forename: Felix
authors.initials: F
authors.lastname: Bacher
authors.forename: Éva  A
authors.initials: É
authors.lastname: Enyedy
authors.forename: Nóra V
authors.initials: NV
authors.lastname: Nagy
authors.forename: Antal
authors.initials: A
authors.lastname: Rockenbauer
authors.forename: Gabriella M
authors.initials: GM
authors.lastname: Bognár
authors.forename: Robert
authors.initials: R
authors.lastname: Trondl
authors.forename: Maria S
authors.initials: MS
authors.lastname: Novak
authors.forename: Erik
authors.initials: E
authors.lastname: Klapproth
authors.forename: Tamás
authors.initials: T
authors.lastname: Kiss
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Arion
mesh_terms: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D003300:Copper / Q000737:chemistry*; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D012709:Serum Albumin / Q000378:metabolism; D012995:Solubility; D013057:Spectrum Analysis; D013237:Stereoisomerism; D013882:Thiosemicarbazones / Q000737:chemistry*; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014867:Water / Q000737:chemistry*
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009942:Organometallic Compounds; D012709:Serum Albumin; D013882:Thiosemicarbazones; D059005:Topoisomerase II Inhibitors; D014867:Water; D003300:Copper; D004250:DNA Topoisomerases, Type II