Dinuclear Iron Complexes of Iminopyridine-Based Ligands as Selective Cytotoxins for Tumor Cells and Inhibitors of Cancer Cell Migration

A family of dinuclear iron (II) compounds with iminopyridine-based ligands displays selective cytotoxic activity against cancer cell lines. All compounds have IC<sub>50</sub> values 2–6 fold lower than that of cisplatin, and 30–90 fold lower than that of carboplatin for the tumor cell li...

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Main Authors: Jessica Castro, Marlon Bravo, Meritxell Albertí, Anaís Marsal, María José Alonso-De Gennaro, Oriol Martínez-Ferraté, Carmen Claver, Piet W. N. M. van Leeuwen, Isabel Romero, Antoni Benito, Maria Vilanova
Format: Article
Language:English
Published: MDPI AG 2022-12-01
Series:Pharmaceutics
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Online Access:https://www.mdpi.com/1999-4923/14/12/2801
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author Jessica Castro
Marlon Bravo
Meritxell Albertí
Anaís Marsal
María José Alonso-De Gennaro
Oriol Martínez-Ferraté
Carmen Claver
Piet W. N. M. van Leeuwen
Isabel Romero
Antoni Benito
Maria Vilanova
author_facet Jessica Castro
Marlon Bravo
Meritxell Albertí
Anaís Marsal
María José Alonso-De Gennaro
Oriol Martínez-Ferraté
Carmen Claver
Piet W. N. M. van Leeuwen
Isabel Romero
Antoni Benito
Maria Vilanova
author_sort Jessica Castro
collection DOAJ
description A family of dinuclear iron (II) compounds with iminopyridine-based ligands displays selective cytotoxic activity against cancer cell lines. All compounds have IC<sub>50</sub> values 2–6 fold lower than that of cisplatin, and 30–90 fold lower than that of carboplatin for the tumor cell lines assayed. Comparing the IC<sub>50</sub> values between tumor and non-tumor cell lines, the selectivity indexes range from 3.2 to 34, compound <b>10, [Fe<sub>2</sub>(4)<sub>2</sub>(CH<sub>3</sub>CN)<sub>4</sub>](BF<sub>4</sub>)<sub>4</sub></b>, showing the highest selectivity. Those compounds carrying substituents on the iminopyridine ring show the same cytotoxicity as those without substituents. However, the electronic effects of the substituents on position 6 may be important for the cytotoxicity of the complexes, and consequently for their selectivity. All compounds act over DNA, promoting cuts on both strands in the presence of reactive oxygen species. Since compound <b>10</b> presented the highest selectivity, its cytotoxic effect was further characterized. It induces apoptosis, affects cell cycle phase distribution in a cell-dependent manner, and its cytotoxic effect is linked to reactive oxygen species generation. In addition, it decreases tumor cell migration, showing potential antimetastatic effects. These properties make compound <b>10</b> a good lead antitumor agent among all compounds studied here.
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spelling doaj.art-f29ae5b972b4413bb0442973889299922023-11-24T17:22:16ZengMDPI AGPharmaceutics1999-49232022-12-011412280110.3390/pharmaceutics14122801Dinuclear Iron Complexes of Iminopyridine-Based Ligands as Selective Cytotoxins for Tumor Cells and Inhibitors of Cancer Cell MigrationJessica Castro0Marlon Bravo1Meritxell Albertí2Anaís Marsal3María José Alonso-De Gennaro4Oriol Martínez-Ferraté5Carmen Claver6Piet W. N. M. van Leeuwen7Isabel Romero8Antoni Benito9Maria Vilanova10Laboratori d’Enginyeria de Proteïnes, Departament de Biologia, Facultat de Ciències, Universitat de Girona, Campus de Montilivi, C/Maria Aurèlia Capmany, 40, 17003 Girona, SpainLaboratori d’Enginyeria de Proteïnes, Departament de Biologia, Facultat de Ciències, Universitat de Girona, Campus de Montilivi, C/Maria Aurèlia Capmany, 40, 17003 Girona, SpainLaboratori d’Enginyeria de Proteïnes, Departament de Biologia, Facultat de Ciències, Universitat de Girona, Campus de Montilivi, C/Maria Aurèlia Capmany, 40, 17003 Girona, SpainLaboratori d’Enginyeria de Proteïnes, Departament de Biologia, Facultat de Ciències, Universitat de Girona, Campus de Montilivi, C/Maria Aurèlia Capmany, 40, 17003 Girona, SpainLaboratori d’Enginyeria de Proteïnes, Departament de Biologia, Facultat de Ciències, Universitat de Girona, Campus de Montilivi, C/Maria Aurèlia Capmany, 40, 17003 Girona, SpainDepartament de Quimica Física e Inorgànica, Universitat Rovira i Virgili, Campus Sescelades, 43007 Tarragona, SpainDepartament de Quimica Física e Inorgànica, Universitat Rovira i Virgili, Campus Sescelades, 43007 Tarragona, SpainInstitut Català d’Investigació Química (ICIQ), Avinguda dels Països Catalans, 16, 43007 Tarragona, SpainDepartament de Química and Serveis Tècnics de Recerca, Universitat de Girona, Campus de Montilivi, C/Maria Aurèlia Capmany, 69, 17003 Girona, SpainLaboratori d’Enginyeria de Proteïnes, Departament de Biologia, Facultat de Ciències, Universitat de Girona, Campus de Montilivi, C/Maria Aurèlia Capmany, 40, 17003 Girona, SpainLaboratori d’Enginyeria de Proteïnes, Departament de Biologia, Facultat de Ciències, Universitat de Girona, Campus de Montilivi, C/Maria Aurèlia Capmany, 40, 17003 Girona, SpainA family of dinuclear iron (II) compounds with iminopyridine-based ligands displays selective cytotoxic activity against cancer cell lines. All compounds have IC<sub>50</sub> values 2–6 fold lower than that of cisplatin, and 30–90 fold lower than that of carboplatin for the tumor cell lines assayed. Comparing the IC<sub>50</sub> values between tumor and non-tumor cell lines, the selectivity indexes range from 3.2 to 34, compound <b>10, [Fe<sub>2</sub>(4)<sub>2</sub>(CH<sub>3</sub>CN)<sub>4</sub>](BF<sub>4</sub>)<sub>4</sub></b>, showing the highest selectivity. Those compounds carrying substituents on the iminopyridine ring show the same cytotoxicity as those without substituents. However, the electronic effects of the substituents on position 6 may be important for the cytotoxicity of the complexes, and consequently for their selectivity. All compounds act over DNA, promoting cuts on both strands in the presence of reactive oxygen species. Since compound <b>10</b> presented the highest selectivity, its cytotoxic effect was further characterized. It induces apoptosis, affects cell cycle phase distribution in a cell-dependent manner, and its cytotoxic effect is linked to reactive oxygen species generation. In addition, it decreases tumor cell migration, showing potential antimetastatic effects. These properties make compound <b>10</b> a good lead antitumor agent among all compounds studied here.https://www.mdpi.com/1999-4923/14/12/2801dinuclear iron (II) compoundsiminopyridine ligandsselectivity for tumor cellscytotoxic mechanismapoptosisinhibition of cell migration
spellingShingle Jessica Castro
Marlon Bravo
Meritxell Albertí
Anaís Marsal
María José Alonso-De Gennaro
Oriol Martínez-Ferraté
Carmen Claver
Piet W. N. M. van Leeuwen
Isabel Romero
Antoni Benito
Maria Vilanova
Dinuclear Iron Complexes of Iminopyridine-Based Ligands as Selective Cytotoxins for Tumor Cells and Inhibitors of Cancer Cell Migration
Pharmaceutics
dinuclear iron (II) compounds
iminopyridine ligands
selectivity for tumor cells
cytotoxic mechanism
apoptosis
inhibition of cell migration
title Dinuclear Iron Complexes of Iminopyridine-Based Ligands as Selective Cytotoxins for Tumor Cells and Inhibitors of Cancer Cell Migration
title_full Dinuclear Iron Complexes of Iminopyridine-Based Ligands as Selective Cytotoxins for Tumor Cells and Inhibitors of Cancer Cell Migration
title_fullStr Dinuclear Iron Complexes of Iminopyridine-Based Ligands as Selective Cytotoxins for Tumor Cells and Inhibitors of Cancer Cell Migration
title_full_unstemmed Dinuclear Iron Complexes of Iminopyridine-Based Ligands as Selective Cytotoxins for Tumor Cells and Inhibitors of Cancer Cell Migration
title_short Dinuclear Iron Complexes of Iminopyridine-Based Ligands as Selective Cytotoxins for Tumor Cells and Inhibitors of Cancer Cell Migration
title_sort dinuclear iron complexes of iminopyridine based ligands as selective cytotoxins for tumor cells and inhibitors of cancer cell migration
topic dinuclear iron (II) compounds
iminopyridine ligands
selectivity for tumor cells
cytotoxic mechanism
apoptosis
inhibition of cell migration
url https://www.mdpi.com/1999-4923/14/12/2801
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