| Autor: |
Pósa V; MTA-SZTE Lendület Functional Metal Complexes Research Group, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary.; Department of Molecular and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7-8, H-6720 Szeged, Hungary., Federa A; Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria.; Research Cluster 'Translational Cancer Therapy Research', Waehringer Strasse 42, A-1090 Vienna, Austria., Cseh K; Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria., Wenisch D; Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria., Spengler G; MTA-SZTE Lendület Functional Metal Complexes Research Group, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary.; Department of Medical Microbiology, Albert Szent-Györgyi Health Center and Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis utca 6, H-6725 Szeged, Hungary., May NV; Centre for Structural Science, Research Centre for Natural Sciences, Hungarian Research Network (HUN-REN), Magyar tudósok körútja 2, H-1117 Budapest, Hungary., Lihi N; ELKH-DE Mechanisms of Complex Homogeneous and Heterogeneous Chemical Reactions Research Group, Department of Inorganic and Analytical Chemistry, University of Debrecen, Egyetem tér 1., H-4032 Debrecen, Hungary., Samu GF; Department of Molecular and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7-8, H-6720 Szeged, Hungary., Jakupec MA; Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria.; Research Cluster 'Translational Cancer Therapy Research', Waehringer Strasse 42, A-1090 Vienna, Austria., Keppler BK; Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria.; Research Cluster 'Translational Cancer Therapy Research', Waehringer Strasse 42, A-1090 Vienna, Austria., Kowol CR; Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, A-1090 Vienna, Austria.; Research Cluster 'Translational Cancer Therapy Research', Waehringer Strasse 42, A-1090 Vienna, Austria., Enyedy ÉA; MTA-SZTE Lendület Functional Metal Complexes Research Group, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary.; Department of Molecular and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7-8, H-6720 Szeged, Hungary. |
| Abstrakt: |
As cancer cells exhibit an increased uptake of iron, targeting the interaction with iron has become a straightforward strategy in the fight against cancer. This work comprehensively characterizes the chemical properties of 6-methyl-3-{(2 E )-2-[1-(2-pyridinyl)ethylidene]hydrazino}-5 H -[1,2,4]triazino[5,6- b ]indole (VLX600), a clinically investigated iron chelator, in solution. Its protonation processes, lipophilicity, and membrane permeability as well as its complexation with essential metal ions were investigated using UV-visible, electron paramagnetic resonance, and NMR spectroscopic and computational methods. Formation constants revealed the following order of metal binding affinity at pH 7.4: Cu(II) > Fe(II) > Zn(II). The structures of VLX600 (denoted as HL) and the coordination modes in its metal complexes [Cu(II)(LH)Cl 2 ], [Cu(II)(L)(CH 3 OH)Cl], [Zn(II)(LH)Cl 2 ], and [Fe(II)(LH) 2 ](NO 3 ) 2 were elucidated by single-crystal X-ray diffraction. Redox properties of the iron complexes characterized by cyclic voltammetry showed strong preference of VLX600 toward Fe(II) over Fe(III). In vitro cytotoxicity of VLX600 was determined in six different human cancer cell lines, with IC 50 values ranging from 0.039 to 0.51 μM. Premixing VLX600 with Fe(III), Zn(II), and Cu(II) salts in stoichiometric ratios had a rather little effect overall, thus neither potentiating nor abolishing cytotoxicity. Together, although clinically investigated as an iron chelator, this is the first comprehensive solution study of VLX600 and its interaction with physiologically essential metal ions. |
