2026-04-20T08:43:40Zhttps://riubu.ubu.es/oai/request

oai:riubu.ubu.es:10259/101922026-01-19T09:16:16Zcom_10259_3844com_10259_5086com_10259_2604col_10259_3845

Sanz Villafruela, Juan Bermejo Casadesus, Cristina Zafon, Elisenda Martínez Alonso, Marta Durá, Gema Heras Vidaurre, Aránzazu Soriano Díaz, Iván Giussani, Angelo Ortí, Enrique . Tebar, Francesc Espino Ordóñez, Gustavo Massaguer Vall-Llovera, Anna 2025-02-10T09:20:47Z 2025-02-10T09:20:47Z 2024-10 0223-5234 http://hdl.handle.net/10259/10192 10.1016/j.ejmech.2024.116618 Ir(III) and Ru(II) polypyridyl complexes are promising photosensitizers (PSs) for photodynamic therapy (PDT) due to their outstanding photophysical properties. Herein, one series of cyclometallated Ir(III) complexes and two series of Ru(II) polypyridyl derivatives bearing three different thiazolyl-β-carboline N^N′ ligands have been synthesized, aiming to evaluate the impact of the different metal fragments ([Ir(C^N)2] + or [Ru(N^N)2] 2+) and N^N’ ligands on the photophysical and biological properties. All the compounds exhibit remarkable photo stability under blue-light irradiation and are emissive (605 < λem < 720 nm), with the Ru(II) derivatives dis playing higher photoluminescence quantum yields and longer excited state lifetimes. The Ir PSs display pKa values between 5.9 and 7.9, whereas their Ru counterparts are less acidic (pKa > 9.3). The presence of the deprotonated form in the Ir-PSs favours the generation of reactive oxygen species (ROS) since, according to theoretical calculations, it features a low-lying ligand-centered triplet excited state (T1 = 3 LC) with a long lifetime. All compounds have demonstrated anticancer activity. Ir(III) complexes 1–3 exhibit the highest cyto toxicity in dark conditions, comparable to cisplatin. Their activity is notably enhanced by blue-light irradiation, resulting in nanomolar IC50 values and phototoxicity indexes (PIs) between 70 and 201 in different cancer cell lines. The Ir(III) PSs are also activated by green (with PI between 16 and 19.2) and red light in the case of complex 3 (PI = 8.5). Their antitumor efficacy is confirmed by clonogenic assays and using spheroid models. The Ir(III) complexes rapidly enter cells, accumulating in mitochondria and lysosomes. Upon photoactivation, they generate ROS, leading to mitochondrial dysfunction and lysosomal damage and ultimately cell apoptosis. Additionally, they inhibit cancer cell migration, a crucial step in metastasis. In contrast, Ru(II) complex 6 exhibits moderate mitochondrial activity. Overall, Ir(III) complexes 1–3 show potential for selective light-controlled cancer treatment, providing an alternative mechanism to chemotherapy and the ability to inhibit lethal cancer cell dissemination. This work was supported by the Ministerio de Ciencia e Innovacion/ ´ Agencia Estatal de Investigacion ´ of Spain (MCIN/AEI/10.13039/ 501100011033) (projects PID2021-127187OB-C21, PID2021- 128569NB-I00, PID2020-115910RB-I00, PID2021-127187OB-C22, and CEX2019-000919-M). PhD students acknowledge their predoctoral grants to Universidad de Burgos (J.S.V., 2019/00002/008/001), Uni versity of Girona (C.B., IFUdG 2021), Generalitat de Catalunya (E.Z., AGAUR; 2021 FI_B 01036) and Generalitat Valenciana (I. S.D., CIACIF/ 2021/438), respectively. application/pdf eng Elsevier European Journal of Medicinal Chemistry. 2024, V. 276, p. 116618 https://doi.org/10.1016/j.ejmech.2024.116618 Atribución 4.0 Internacional http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess Cancer Photodynamic therapy Cyclometalated complexes Mitochondria Química analítica Bioquímica Chemistry, Analytic Biochemistry Insights into the anticancer photodynamic activity of Ir(III) and Ru(II) polypyridyl complexes bearing β-carboline ligands info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion European Journal of Medicinal Chemistry 276 116618