2. Academic Validation
  3. First iron(II) organometallic compound acting as ABCB1 inhibitor

First iron(II) organometallic compound acting as ABCB1 inhibitor

  • Eur J Med Chem. 2023 Aug 5:256:115466. doi: 10.1016/j.ejmech.2023.115466.
Adhan Pilon 1,  Fernando Avecilla 2,  Miklós Mohai 3,  Éva A Enyedy 4,  Bálint Rácz 5,  Gabriella Spengler 5,  M Helena Garcia 1,  Andreia Valente 6
Affiliations

Affiliations

  • 1 Centro de Química Estrutural, Institute of Molecular Sciences and Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016, Lisboa, Portugal.
  • 2 Universidade da Coruña, Grupo NanoToxGen, Centro Interdisciplinar de Química y Biología (CICA), Departamento de Química, Facultade de Ciencias, Campus de A Coruña, 15071, A Coruña, Spain.
  • 3 Research Centre for Natural Sciences, Institute of Materials and Environmental Chemistry, Magyar tudósok körútja 2, H-1117, Budapest, Hungary.
  • 4 MTA-SZTE Lendület Functional Metal Complexes Research Group, Department of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7, H-6720, Szeged, Hungary.
  • 5 Department of Medical Microbiology, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis utca 6, H-6725, Szeged, Hungary.
  • 6 Centro de Química Estrutural, Institute of Molecular Sciences and Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016, Lisboa, Portugal. Electronic address: amvalente@ciencias.ulisboa.pt.
PMID: 37187089 DOI: 10.1016/j.ejmech.2023.115466
Abstract

Five new iron (II) complexes bearing imidazole-based (Imi-R) ligands with the general formula [Fe(η5-C5H5)(CO)(PPh3)(Imi-R)][CF3SO3] were synthesized and fully characterized by several spectroscopic and analytical techniques. All compounds crystallize in centrosymmetric space groups in a typical "piano stool" distribution. Given the growing importance of finding alternatives to overcome different forms of multidrug resistance, all compounds were tested against Cancer cell lines with different ABCB1 efflux pump expression, namely, the doxorubicin-sensitive (Colo205) and doxorubicin-resistant (Colo320) human colon adenocarcinoma cell lines. Compound 3 bearing 1-benzylimidazole was the most active in both cell lines with IC50 values of 1.26 ± 0.11 and 2.21 ± 0.26 μM, respectively, being also slightly selective against the Cancer cells (vs. MRC5 normal human embryonic fibroblast cell lines). This compound, together with compound 2 bearing 1H-1,3-benzodiazole, were found to display very potent ABCB1 inhibitory effect. Compound 3 also showed the ability to induce cell Apoptosis. Iron cellular accumulation studies by ICP-MS and ICP-OES methods revealed that the compounds' cytotoxicity is not related to the extent of iron accumulation. Yet, it is worth mentioning that, from the compounds tested, 3 was the only one where iron accumulation was greater in the resistant cell line than in the sensitive one, validating the possible role of ABCB1 inhibition in its mechanism of action.

Keywords

ABCB1 inhibitor; Cancer multidrug resistance; Colon adenocarcinoma; Iron-cyclopentadienyl.

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