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Targets, Mechanisms and Cytotoxicity of Half-Sandwich Ir(III) Complexes Are Modulated by Structural Modifications on the Benzazole Ancillary Ligand

SIMPLE SUMMARY: Iridium complexes have been reported as potential drug candidates for the treatment of cancer. They are easy to prepare, and their structure allows several modifications that make them extremely versatile as metallodrugs. Thus, the aim of this work was to get a structure–activity rel...

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Autores principales: Acuña, M. Isabel, Rubio, Ana R., Martínez-Alonso, Marta, Busto, Natalia, Rodríguez, Ana María, Davila-Ferreira, Nerea, Smythe, Carl, Espino, Gustavo, García, Begoña, Domínguez, Fernando
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9818021/
https://www.ncbi.nlm.nih.gov/pubmed/36612104
http://dx.doi.org/10.3390/cancers15010107
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author Acuña, M. Isabel
Rubio, Ana R.
Martínez-Alonso, Marta
Busto, Natalia
Rodríguez, Ana María
Davila-Ferreira, Nerea
Smythe, Carl
Espino, Gustavo
García, Begoña
Domínguez, Fernando
author_facet Acuña, M. Isabel
Rubio, Ana R.
Martínez-Alonso, Marta
Busto, Natalia
Rodríguez, Ana María
Davila-Ferreira, Nerea
Smythe, Carl
Espino, Gustavo
García, Begoña
Domínguez, Fernando
author_sort Acuña, M. Isabel
collection PubMed
description SIMPLE SUMMARY: Iridium complexes have been reported as potential drug candidates for the treatment of cancer. They are easy to prepare, and their structure allows several modifications that make them extremely versatile as metallodrugs. Thus, the aim of this work was to get a structure–activity relationship study to check the structural versatility of a series of iridium(III) complexes and the way it affects their behavior in both their intrinsic features and inside cells. The most promising complex 1[C,NH], showing cyclometallation, targets mitochondria—the cell powerhouse—triggering cell death through mitochondrial membrane depolarization and proton leak. Moreover, in vivo studies in mice confirmed the reduction of the tumor burden. These findings could guide the future design of next generation anticancer drugs able to avoid resistance, as to date, no cancer chemoresistance mechanism can overcome mitochondrial dysfunction. ABSTRACT: Cancers are driven by multiple genetic mutations but evolve to evade treatments targeting specific mutations. Nonetheless, cancers cannot evade a treatment that targets mitochondria, which are essential for tumor progression. Iridium complexes have shown anticancer properties, but they lack specificity for their intracellular targets, leading to undesirable side effects. Herein we present a systematic study on structure-activity relationships of eight arylbenzazole-based Iridium(III) complexes of type [IrCl(Cp*)], that have revealed the role of each atom of the ancillary ligand in the physical chemistry properties, cytotoxicity and mechanism of biological action. Neutral complexes, especially those bearing phenylbenzimidazole (HL1 and HL2), restrict the binding to DNA and albumin. One of them, complex 1[C,NH-Cl], is the most selective one, does not bind DNA, targets exclusively the mitochondria, disturbs the mitochondria membrane permeability inducing proton leak and increases ROS levels, triggering the molecular machinery of regulated cell death. In mice with orthotopic lung tumors, the administration of complex 1[C,NH-Cl] reduced the tumor burden. Cancers are more vulnerable than normal tissues to a treatment that harnesses mitochondrial dysfunction. Thus, complex 1[C,NH-Cl] characterization opens the way to the development of new compounds to exploit this vulnerability.
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spelling pubmed-98180212023-01-07 Targets, Mechanisms and Cytotoxicity of Half-Sandwich Ir(III) Complexes Are Modulated by Structural Modifications on the Benzazole Ancillary Ligand Acuña, M. Isabel Rubio, Ana R. Martínez-Alonso, Marta Busto, Natalia Rodríguez, Ana María Davila-Ferreira, Nerea Smythe, Carl Espino, Gustavo García, Begoña Domínguez, Fernando Cancers (Basel) Article SIMPLE SUMMARY: Iridium complexes have been reported as potential drug candidates for the treatment of cancer. They are easy to prepare, and their structure allows several modifications that make them extremely versatile as metallodrugs. Thus, the aim of this work was to get a structure–activity relationship study to check the structural versatility of a series of iridium(III) complexes and the way it affects their behavior in both their intrinsic features and inside cells. The most promising complex 1[C,NH], showing cyclometallation, targets mitochondria—the cell powerhouse—triggering cell death through mitochondrial membrane depolarization and proton leak. Moreover, in vivo studies in mice confirmed the reduction of the tumor burden. These findings could guide the future design of next generation anticancer drugs able to avoid resistance, as to date, no cancer chemoresistance mechanism can overcome mitochondrial dysfunction. ABSTRACT: Cancers are driven by multiple genetic mutations but evolve to evade treatments targeting specific mutations. Nonetheless, cancers cannot evade a treatment that targets mitochondria, which are essential for tumor progression. Iridium complexes have shown anticancer properties, but they lack specificity for their intracellular targets, leading to undesirable side effects. Herein we present a systematic study on structure-activity relationships of eight arylbenzazole-based Iridium(III) complexes of type [IrCl(Cp*)], that have revealed the role of each atom of the ancillary ligand in the physical chemistry properties, cytotoxicity and mechanism of biological action. Neutral complexes, especially those bearing phenylbenzimidazole (HL1 and HL2), restrict the binding to DNA and albumin. One of them, complex 1[C,NH-Cl], is the most selective one, does not bind DNA, targets exclusively the mitochondria, disturbs the mitochondria membrane permeability inducing proton leak and increases ROS levels, triggering the molecular machinery of regulated cell death. In mice with orthotopic lung tumors, the administration of complex 1[C,NH-Cl] reduced the tumor burden. Cancers are more vulnerable than normal tissues to a treatment that harnesses mitochondrial dysfunction. Thus, complex 1[C,NH-Cl] characterization opens the way to the development of new compounds to exploit this vulnerability. MDPI 2022-12-24 /pmc/articles/PMC9818021/ /pubmed/36612104 http://dx.doi.org/10.3390/cancers15010107 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Acuña, M. Isabel
Rubio, Ana R.
Martínez-Alonso, Marta
Busto, Natalia
Rodríguez, Ana María
Davila-Ferreira, Nerea
Smythe, Carl
Espino, Gustavo
García, Begoña
Domínguez, Fernando
Targets, Mechanisms and Cytotoxicity of Half-Sandwich Ir(III) Complexes Are Modulated by Structural Modifications on the Benzazole Ancillary Ligand
title Targets, Mechanisms and Cytotoxicity of Half-Sandwich Ir(III) Complexes Are Modulated by Structural Modifications on the Benzazole Ancillary Ligand
title_full Targets, Mechanisms and Cytotoxicity of Half-Sandwich Ir(III) Complexes Are Modulated by Structural Modifications on the Benzazole Ancillary Ligand
title_fullStr Targets, Mechanisms and Cytotoxicity of Half-Sandwich Ir(III) Complexes Are Modulated by Structural Modifications on the Benzazole Ancillary Ligand
title_full_unstemmed Targets, Mechanisms and Cytotoxicity of Half-Sandwich Ir(III) Complexes Are Modulated by Structural Modifications on the Benzazole Ancillary Ligand
title_short Targets, Mechanisms and Cytotoxicity of Half-Sandwich Ir(III) Complexes Are Modulated by Structural Modifications on the Benzazole Ancillary Ligand
title_sort targets, mechanisms and cytotoxicity of half-sandwich ir(iii) complexes are modulated by structural modifications on the benzazole ancillary ligand
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9818021/
https://www.ncbi.nlm.nih.gov/pubmed/36612104
http://dx.doi.org/10.3390/cancers15010107
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