Effects of Terminal Dimethylation and Metal Coordination of Proline-2-formylpyridine Thiosemicarbazone Hybrids on Lipophilicity, Antiproliferative Activity, and hR2 RNR Inhibition

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• 作者：Felix Bacher ; Orsolya D枚m枚t枚r ; Maria Kaltenbrunner ; Milo拧 Mojovi膰 ; Ana Popovi膰-Bijeli膰 ; Astrid Gr盲slund ; Andrew Ozarowski ; Lana Filipovic ; Sinisa Radulovi膰 ; 脡va A. Enyedy ; Vladimir B. Arion
• 刊名：Inorganic Chemistry
• 出版年：2014
• 出版时间：December 1, 2014
• 年：2014
• 卷：53
• 期：23
• 页码：12595-12609
• 全文大小：807K
• ISSN：1520-510X

文摘

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鈥?H)]₂ (1), [Ni(d-Pro-FTSC鈥?H)]₂ (2), [Ni(dm-l-Pro-FTSC鈥?H)]₂ (3), [Cu(dm-l-Pro-FTSC鈥?H)] (6), [Zn(l-Pro-FTSC鈥?H)] (7), and [Zn(d-Pro-FTSC鈥?H)] (8), in addition to two previously reported, [Cu(l-Pro-FTSC鈥?H)] (4), [Cu(d-Pro-FTSC鈥?H)] (5), were synthesized and characterized by elemental analysis, one- and two-dimensional ¹H and ¹³C NMR spectroscopy, circular dichroism, UV鈥搗is, and electrospray ionization mass spectrometry. Compounds 1鈥?b>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鈥?20 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鈥搗is, 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.