Are the metal identity and stoichiometry of metal complexes important for colchicine site binding and inhibition of tubulin polymerization?

Iuliana Besleaga; Renáta Raptová; Alexandru-Constantin Stoica; Miljan N. M. Milunovic; Michal Zalibera; Ruoli Bai; Nóra Igaz; Jóhannes Reynisson; Mónika Kiricsi; Éva A. Enyedy; Peter Rapta; Ernest Hamel; Vladimir B. Arion

doi:10.1039/D4DT01469C

Are the metal identity and stoichiometry of metal complexes important for colchicine site binding and inhibition of tubulin polymerization?†

Iuliana Besleaga,

^a Renáta Raptová,^bc Alexandru-Constantin Stoica,

^d Miljan N. M. Milunovic,

*^a Michal Zalibera,

^b Ruoli Bai,^e Nóra Igaz,^f Jóhannes Reynisson,

^g Mónika Kiricsi,^g Éva A. Enyedy,

*^hi Peter Rapta,^b Ernest Hamel

^e and Vladimir B. Arion

*^ad

Author affiliations

* Corresponding authors

^a Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Währinger Straße 42, A-1090 Vienna, Austria
E-mail: miljan.milunovic@univie.ac.at, vladimir.arion@univie.ac.at

^b Institute of Physical Chemistry and Chemical Physics, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, SK-81237 Bratislava, Slovakia

^c Institute of Physical and Theoretical Chemistry, Graz University of Technology, Stremayrgasse 9/II, A-8010 Graz, Austria

^d Inorganic Polymers Department, “Petru Poni” Institute of Macromolecular Chemistry, Aleea Gr. Ghica Voda 41 A, Iasi 700487, Romania

^e Molecular Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Diagnosis and Treatment, National Cancer Institute, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, Maryland 21702, USA

^f Department of Biochemistry and Molecular Biology, University of Szeged, Közép fasor 52, H-6726 Szeged, Hungary

^g School of Pharmacy and Bioengineering, Keele University, Newcastle-under-Lyme, Staffordshire ST5 5BG, UK

^h Department of Molecular and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7-8, H-6720 Szeged, Hungary
E-mail: enyedy@chem.u-szeged.hu

ⁱ MTA-SZTE Lendület Functional Metal Complexes Research Group, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary

Abstract

Quite recently we discovered that copper(II) complexes with isomeric morpholine-thiosemicarbazone hybrid ligands show good cytotoxicity in cancer cells and that the molecular target responsible for this activity might be tubulin. In order to obtain better lead drug candidates, we opted to exploit the power of coordination chemistry to (i) assemble structures with globular shape to better fit the colchicine pocket and (ii) vary the metal ion. We report the synthesis and full characterization of bis-ligand cobalt(III) and iron(III) complexes with 6-morpholinomethyl-2-formylpyridine 4N-(4-hydroxy-3,5-dimethylphenyl)-3-thiosemicarbazone (HL¹), 6-morpholinomethyl-2-acetylpyridine 4N-(4-hydroxy-3,5-dimethylphenyl)-3-thiosemicarbazone (HL²), and 6-morpholinomethyl-2-formylpyridine 4N-phenyl-3-thiosemicarbazone (HL³), and mono-ligand nickel(II), zinc(II) and palladium(II) complexes with HL¹, namely [Co^III(HL¹)(L¹)](NO₃)₂ (1), [Co^III(HL²)(L²)](NO₃)₂ (2), [Co^III(HL³)(L³)](NO₃)₂ (3), [Fe^III(L²)₂]NO₃ (4), [Fe^III(HL³)(L³)](NO₃)₂ (5), [Ni^II(L¹)]Cl (6), [Zn(L¹)Cl] (7) and [Pd^II(HL¹)Cl]Cl (8). We discuss the effect of the metal identity and metal complex stoichiometry on in vitro cytotoxicity and antitubulin activity. The high antiproliferative activity of complex 4 correlated well with inhibition of tubulin polymerization. Insights into the mechanism of antiproliferative activity were supported by experimental results and molecular docking calculations.

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Are the metal identity and stoichiometry of metal complexes important for colchicine site binding and inhibition of tubulin polymerization?†

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Are the metal identity and stoichiometry of metal complexes important for colchicine site binding and inhibition of tubulin polymerization?

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