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oai:riubu.ubu.es:10259/75612023-04-19T08:00:45Zcom_10259_4365com_10259_5086com_10259_2604com_10259_4363com_10259_6185com_10259_3591com_10259.4_106col_10259_4366col_10259_4364col_10259_6186

2023-03-20T10:47:17Z urn:hdl:10259/7561 Targets, Mechanisms and Cytotoxicity of Half-Sandwich Ir(III) Complexes Are Modulated by Structural Modifications on the Benzazole Ancillary Ligand Acuña, M. Isabel Rubio Antolin, Ana Rosa Martínez Alonso, Marta Busto Vázquez, Natalia Rodríguez, Ana María Davila Ferreira, Nerea Smythe, Carl Espino Ordóñez, Gustavo García Ruiz, Begoña Domínguez, Fernando Organometallic iridium complex DNA binding Mitochondrial damage Proton leak Apoptosis 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 2023-03-20T10:47:17Z 2023-03-20T10:47:17Z 2022-12 info:eu-repo/semantics/article http://hdl.handle.net/10259/7561 10.3390/cancers15010107 2072-6694 eng Cancers. 2022, V. 15, n. 1, 107 https://doi.org/10.3390/cancers15010107 info:eu-repo/grantAgreement/Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona//LCF%2FPR%2FPR12%2F11070003// info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-102040-B-I00/ES/PROPIEDADES ANTIMICROBIANAS DE NUEVOS COMPLEJOS ORGANOMETALICOS/ info:eu-repo/grantAgreement/Junta de Castilla y León//BU305P18//DISEÑO Y CARACTERIZACIÓN DE COMPLEJOS BIOINORGÁNICOS Y CLÚSTERES CUÁNTICOS ATÓMICOS. PROPIEDADES ANTIMICROBIANAS EN CEPAS RESISTENTES. PROPIEDADES ANTITUMORALES EN LA OSCURIDAD Y BAJO IRRADIACIÓN/ info:eu-repo/grantAgreement/COST//CA18202/EU/Network for Equilibria and Chemical Thermodynamics Advanced Research/NECTAR/ http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess Atribución 4.0 Internacional MDPI