Effects of terminal dimethylation and metal coordination of proline-2-formylpyridine thiosemicarbazone hybrids on lipophilicity, antiproliferative activity, and hR2 RNR inhibition

Felix Bacher, Orsolya Dömötör, Maria Kaltenbrunner, Miloš Mojović, Ana Popović-Bijelić, Astrid Gräslund, Andrew Ozarowski, Lana Filipovic, Sinisa Radulović, Éva A. Enyedy, Vladimir B. Arion

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Abstract

The nickel(II), copper(II), and zinc(II) complexes of the proline-thiosemicarbazone hybrids 3-methyl-(S)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone (l-Pro-FTSC or (S)-H2L1) and 3-methyl-(R)-pyrrolidine-2-carboxylate-2-formylpyridine thiosemicarbazone (d-Pro-FTSC or (R)-H2L1), as well as 3-methyl-(S)-pyrrolidine-2-carboxylate-2-formylpyridine 4,4-dimethyl-thiosemicarbazone (dm-l-Pro-FTSC or (S)-H2L2), namely, [Ni(l-Pro-FTSC-2H)]2 (1), [Ni(d-Pro-FTSC-2H)]2 (2), [Ni(dm-l-Pro-FTSC-2H)]2 (3), [Cu(dm-l-Pro-FTSC-2H)] (6), [Zn(l-Pro-FTSC-2H)] (7), and [Zn(d-Pro-FTSC-2H)] (8), in addition to two previously reported, [Cu(l-Pro-FTSC-2H)] (4), [Cu(d-Pro-FTSC-2H)] (5), were synthesized and characterized by elemental analysis, one- and two-dimensional 1H and 13C NMR spectroscopy, circular dichroism, UV-vis, and electrospray ionization mass spectrometry. Compounds 1-3, 6, and 7 were also studied by single-crystal X-ray diffraction. Magnetic properties and solid-state high-field electron paramagnetic resonance spectra of 2 over the range of 50-420 GHz were investigated. The complex formation processes of l-Pro-FTSC with nickel(II) and zinc(II) were studied in aqueous solution due to the excellent water solubility of the complexes via pH potentiometry, UV-vis, and 1H NMR spectroscopy. The results of the antiproliferative activity in vitro showed that dimethylation improves the cytotoxicity and hR2 RNR inhibition. Therefore, introduction of more lipophilic groups into thiosemicarbazone-proline backbone becomes an option for the synthesis of more efficient cytotoxic agents of this family of compounds.

Original languageEnglish
Pages (from-to)12595-12609
Number of pages15
JournalInorganic Chemistry
Volume53
Issue number23
DOIs
Publication statusPublished - Dec 1 2014

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Inorganic Chemistry

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    Bacher, F., Dömötör, O., Kaltenbrunner, M., Mojović, M., Popović-Bijelić, A., Gräslund, A., Ozarowski, A., Filipovic, L., Radulović, S., Enyedy, É. A., & Arion, V. B. (2014). Effects of terminal dimethylation and metal coordination of proline-2-formylpyridine thiosemicarbazone hybrids on lipophilicity, antiproliferative activity, and hR2 RNR inhibition. Inorganic Chemistry, 53(23), 12595-12609. https://doi.org/10.1021/ic502239u