A Comparative Study on the Complexation of the Anticancer Iron Chelator VLX600 with Essential Metal Ions
- Author(s)
- Vivien Pósa, Anja Federa, Klaudia Cseh, Dominik Wenisch, Gabriella Spengler, Nóra V. May, Norbert Lihi, Gergely F. Samu, Michael A. Jakupec, Bernhard K. Keppler, Christian R. Kowol, Éva A. Enyedy
- Abstract
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-{(2E)-2-[1-(2-pyridinyl)ethylidene]hydrazino}-5H-[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)Cl2], [Cu(II)(L)(CH3OH)Cl], [Zn(II)(LH)Cl2], and [Fe(II)(LH)2](NO3)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 IC50 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.
- Organisation(s)
- Department of Inorganic Chemistry
- External organisation(s)
- University of Szeged, Research Cluster Translational Cancer Therapy Research, Hungarian Academy of Sciences, University of Debrecen
- Journal
- Inorganic Chemistry
- Volume
- 63
- Pages
- 2401-2417
- No. of pages
- 17
- ISSN
- 0020-1669
- DOI
- https://doi.org/10.1021/acs.inorgchem.3c03259
- Publication date
- 02-2024
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 104003 Inorganic chemistry, 301904 Cancer research
- ASJC Scopus subject areas
- Physical and Theoretical Chemistry, Inorganic Chemistry
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/20d98a36-9b1f-4af8-a518-88282585a364