Article

Metal Complexes of a 5-Nitro-8-Hydroxyquinoline-Proline Hybrid with Enhanced Water Solubility Targeting Multidrug Resistant Cancer Cells

Tamás PivarcsikDepartment of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7, H-6720 Szeged, HungaryVivien PósaDepartment of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7, H-6720 Szeged, HungaryHilda KovácsDepartment of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7, H-6720 Szeged, HungaryNóra V. MayCentre for Structural Science, Research Centre for Natural Sciences, Eötvös Loránd Research Network, Magyar Tudósok krt. 2, H-1117 Budapest, HungaryGabriella SpenglerDepartment of Medical Microbiology, Albert Szent-Györgyi Health Center, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis u. 6, H-6725 Szeged, HungarySzonja Polett PósaDrug Resistance Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Eötvös Loránd Research Network, Magyar Tudósok krt. 2, H-1117 Budapest, HungarySzilárd TóthDrug Resistance Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Eötvös Loránd Research Network, Magyar Tudósok krt. 2, H-1117 Budapest, HungaryZeinab Nezafat YazdiDrug Resistance Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Eötvös Loránd Research Network, Magyar Tudósok krt. 2, H-1117 Budapest, HungaryCsilla Özvegy‐LaczkaDrug Resistance Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Eötvös Loránd Research Network, Magyar Tudósok krt. 2, H-1117 Budapest, HungaryImre UgraiInstitute of Pharmaceutical Chemistry and Stereochemistry Research Group, Eötvös Loránd Research Network, University of Szeged, Eötvös u. 6, H-6720 Szeged, HungaryIstván SzatmáriInstitute of Pharmaceutical Chemistry and Stereochemistry Research Group, Eötvös Loránd Research Network, University of Szeged, Eötvös u. 6, H-6720 Szeged, HungaryGergely SzakácsDrug Resistance Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Eötvös Loránd Research Network, Magyar Tudósok krt. 2, H-1117 Budapest, HungaryÉva A. EnyedyDepartment of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary

2022en

ABI

Abstract

Multidrug resistance (MDR) in cancer is one of the major obstacles of chemotherapy. We have recently identified a series of 8-hydroxyquinoline Mannich base derivatives with MDR-selective toxicity, however with limited solubility. In this work, a novel 5-nitro-8-hydroxyquinoline-proline hybrid and its Rh(η5-C5Me5) and Ru(η6-p-cymene) complexes with excellent aqueous solubility were developed, characterized, and tested against sensitive and MDR cells. Complex formation of the ligand with essential metal ions was also investigated using UV-visible, circular dichroism, 1H NMR (Zn(II)), and electron paramagnetic resonance (Cu(II)) spectroscopic methods. Formation of mono and bis complexes was found in all cases with versatile coordination modes, while tris complexes were also formed with Fe(II) and Fe(III) ions, revealing the metal binding affinity of the ligand at pH 7.4: Cu(II) > Zn(II) > Fe(II) > Fe(III). The ligand and its Rh(III) complex displayed enhanced cytotoxicity against the resistant MES-SA/Dx5 and Colo320 human cancer cell lines compared to their chemosensitive counterparts. Both organometallic complexes possess high stability in solution, however the Ru(II) complex has lower chloride ion affinity and slower ligand exchange processes, along with the readiness to lose the arene ring that is likely connected to its inactivity.

Identifiers

DOI: 10.3390/ijms24010593

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Cited by 20 references

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