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Insights into the anticancer photodynamic activity of Ir(III) and Ru(II) polypyridyl complexes bearing β-carboline ligands.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2024 Oct 05; Vol. 276, pp. 116618. Date of Electronic Publication: 2024 Jun 28. - Publication Year :
- 2024
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Abstract
- 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) <subscript>2</subscript> ] <superscript>+</superscript> or [Ru(N^N) <subscript>2</subscript> ] <superscript>2+</superscript> ) and N^N' ligands on the photophysical and biological properties. All the compounds exhibit remarkable photostability under blue-light irradiation and are emissive (605 < λ <subscript>em</subscript>  < 720 nm), with the Ru(II) derivatives displaying higher photoluminescence quantum yields and longer excited state lifetimes. The Ir PSs display pK <subscript>a</subscript> values between 5.9 and 7.9, whereas their Ru counterparts are less acidic (pK <subscript>a</subscript> > 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 (T <subscript>1</subscript>  =  <superscript>3</superscript> LC) with a long lifetime. All compounds have demonstrated anticancer activity. Ir(III) complexes 1-3 exhibit the highest cytotoxicity in dark conditions, comparable to cisplatin. Their activity is notably enhanced by blue-light irradiation, resulting in nanomolar IC <subscript>50</subscript> 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.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Subjects :
- Humans
Ligands
Molecular Structure
Structure-Activity Relationship
Cell Proliferation drug effects
Pyridines chemistry
Pyridines pharmacology
Pyridines chemical synthesis
Reactive Oxygen Species metabolism
Dose-Response Relationship, Drug
Cell Line, Tumor
Cell Survival drug effects
Apoptosis drug effects
Iridium chemistry
Iridium pharmacology
Ruthenium chemistry
Ruthenium pharmacology
Antineoplastic Agents pharmacology
Antineoplastic Agents chemistry
Antineoplastic Agents chemical synthesis
Photosensitizing Agents pharmacology
Photosensitizing Agents chemistry
Photosensitizing Agents chemical synthesis
Coordination Complexes pharmacology
Coordination Complexes chemistry
Coordination Complexes chemical synthesis
Photochemotherapy
Carbolines chemistry
Carbolines pharmacology
Carbolines chemical synthesis
Drug Screening Assays, Antitumor
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 276
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38972079
- Full Text :
- https://doi.org/10.1016/j.ejmech.2024.116618