| 1. |
- Bacher, Felix, et al.
(author)
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Effects of Terminal Dimethylation and Metal Coordination of Proline-2-formylpyridine Thiosemicarbazone Hybrids on Lipophilicity, Antiproliferative Activity, and hR2 RNR Inhibition
- 2014
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In: Inorganic Chemistry. - : American Chemical Society (ACS). - 0020-1669 .- 1520-510X. ; 53:23, s. 12595-12609
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Journal article (peer-reviewed)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 (1)H and (13)C 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 (1)H 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.
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| 2. |
- Eberhardt, Mirjam, et al.
(author)
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H2S and NO cooperatively regulate vascular tone by activating a neuroendocrine HNO-TRPA1-CGRP signalling pathway.
- 2014
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5:Jul 15
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Journal article (peer-reviewed)abstract
- Nitroxyl (HNO) is a redox sibling of nitric oxide (NO) that targets distinct signalling pathways with pharmacological endpoints of high significance in the treatment of heart failure. Beneficial HNO effects depend, in part, on its ability to release calcitonin gene-related peptide (CGRP) through an unidentified mechanism. Here we propose that HNO is generated as a result of the reaction of the two gasotransmitters NO and H2S. We show that H2S and NO production colocalizes with transient receptor potential channel A1 (TRPA1), and that HNO activates the sensory chemoreceptor channel TRPA1 via formation of amino-terminal disulphide bonds, which results in sustained calcium influx. As a consequence, CGRP is released, which induces local and systemic vasodilation. H2S-evoked vasodilatatory effects largely depend on NO production and activation of HNO-TRPA1-CGRP pathway. We propose that this neuroendocrine HNO-TRPA1-CGRP signalling pathway constitutes an essential element for the control of vascular tone throughout the cardiovascular system.
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