A Ruthenium(II) Complex Containing a Redox-Active Semiquinonate Ligand as Potential Chemotherapeutic Agent: From Synthesis to In Vivo Studies
| Autor: | Nils Rotthowe, Marta Jakubaszek, Riccardo Rubbiani, Fethi Bedioui, Mickaël Tharaud, Severin Koch, Martina Řezáčová, Jana Humajova, Cristina Mari, Bruno Goud, Angelo Frei, Pavel Tomsik, Jérémie Gouyon, Gilles Gasser, Anna Notaro, Olivier Blacque, Rainer F. Winter, Mazzarine Dotou, Stefano Ferrari, Uttara Basu |
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| Přispěvatelé: | Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL), Universität Zürich [Zürich] = University of Zurich (UZH), Mécanismes moléculaires du transport intracellulaire, Compartimentation et dynamique cellulaires (CDC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut de Physique du Globe de Paris (IPGP), Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS), Europeen ERC Grant, European Project: 681679, H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC),681679,PhotoMedMet(2017), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut national des sciences de l'Univers (INSU - CNRS)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Drug
media_common.quotation_subject Medicinal Inorganic Chemistry chemistry.chemical_element [CHIM.THER]Chemical Sciences/Medicinal Chemistry 010402 general chemistry 01 natural sciences chemistry.chemical_compound In vivo Drug Discovery medicine Moiety Redox active [CHIM]Chemical Sciences Bioinorganic Chemistry media_common Cancer Cisplatin 010405 organic chemistry Biological activity Ligand (biochemistry) medicine.disease Combinatorial chemistry In vitro 0104 chemical sciences Ruthenium 3. Good health chemistry Molecular Medicine Chemotherapeutic drugs Growth inhibition medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry Journal of Medicinal Chemistry, 2020, ⟨10.1021/acs.jmedchem.0c00431⟩ Journal of Medicinal Chemistry, American Chemical Society, 2020, ⟨10.1021/acs.jmedchem.0c00431⟩ |
| ISSN: | 0022-2623 1520-4804 |
| DOI: | 10.1021/acs.jmedchem.0c00431⟩ |
| Popis: | Chemotherapy remains one of the dominant treatments to cure cancer. However, due to the many inherent drawbacks, there is a surge for new chemotherapeutic drugs. More specifically, the discovery of new drug candidates able to overcome severe side effects, the occurrence of resistance and the inefficacy toward metastatic tumours is highly desirable. In this work, we designed a new chemotherapeutic drug candidate against cancer, namely [Ru(DIP)2(sq)]PF6 (Ru-sq) (DIP = 4,7-diphenyl-1,10-phenanthroline; sq = semiquinonate ligand). The aim was to combine the great potential expressed by Ru(II) polypyridyl complexes and the singular redox and biological properties associated to the catecholate moiety. Several pieces of experimental evidence (e.g., X-ray crystallography, electron paramagnetic resonance, electrochemistry) demonstrate that the semiquinonate is the preferred oxidation state of the dioxo ligand in this complex. The biological activity of Ru-sq was then scrutinised in vitro and in vivo, and the results highlight the tremendous potential of this complex as a chemotherapeutic agent against cancer. Ru-sq was notably found have a much higher cytotoxic activity than cisplatin on several cell lines (i.e. in the nanomolar range), and, contrary to cisplatin, to have mitochondrial disfunction as one of its modes of action. The multicellular targets of Ru-sq could potentially be the key to overcome one of the main drawbacks of cisplatin i.e. the occurrence of resistance. Moreover, Ru-sq exhibited impressing activity on Multi Cellular Tumour Spheroids (MCTS) model, leading to a growth inhibition of the tumour even 13 days after treatment (20 μM). Very importantly, using two different in vivo models, it could be demonstrated that this compound is extremely well-tolerated by mice and has a very promising activity, curing, in some cases, tumour-bearing mice. |
| Databáze: | OpenAIRE |
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