TY - JOUR
T1 - A Comparative Study on the Complexation of the Anticancer Iron Chelator VLX600 with Essential Metal Ions
AU - Pósa, Vivien
AU - Federa, Anja
AU - Cseh, Klaudia
AU - Wenisch, Dominik
AU - Spengler, Gabriella
AU - May, Nóra V.
AU - Lihi, Norbert
AU - Samu, Gergely F.
AU - Jakupec, Michael A.
AU - Keppler, Bernhard K.
AU - Kowol, Christian R.
AU - Enyedy, Éva A.
N1 - Accession Number: WOS:001158211000001
PubMed ID: 38265361
PY - 2024/2/14
Y1 - 2024/2/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85184295538&partnerID=8YFLogxK
U2 - 10.1021/acs.inorgchem.3c03259
DO - 10.1021/acs.inorgchem.3c03259
M3 - Article
C2 - 38265361
AN - SCOPUS:85184295538
VL - 63
SP - 2401
EP - 2417
JO - Inorganic Chemistry
JF - Inorganic Chemistry
SN - 0020-1669
IS - 5
ER -
