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NMR investigation of cellular targets and mechanistic profiles of ruthenium-based drugs

English title NMR investigation of cellular targets and mechanistic profiles of ruthenium-based drugs
Applicant Furrer Julien
Number 131867
Funding scheme Project funding (Div. I-III)
Research institution Departement für Chemie und Biochemie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Inorganic Chemistry
Start/End 01.01.2011 - 31.12.2012
Approved amount 142'897.00
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All Disciplines (2)

Discipline
Inorganic Chemistry
Physical Chemistry

Keywords (8)

Ruthenium complexes; Cancer; Drug; NMR; HRMAS; Structural studies; ruthenium-based anticancer drugs; NMR Spectroscopy

Lay Summary (English)

Lead
Lay summary
Unless platinum drugs which are long known to be also toxic to normal tissues, rutheniumbased drugs possess several favorable chemical properties indicating that some of them may be strong candidates to supplant those platinum-based drugs.1 Currently, two ruthenium-based anticancer drugs,NAMI-A2 and KP10193 have successfully completed phase I clinical trials and have entered phase II.NAMI-A appeared to be effective against lung metastases, whereas KP1019 showed activity against colon carcinomas and their metastases.4 Thus, ruthenium-based complexes form a basis for rational anticancer drug design. Several studies have revealed that most arene ruthenium complexes bind covalently to DNA via the N atom of purines and cause cytoxicity by inhibiting cellular DNAsynthesis.5 Moreover, ruthenium complexes have a strong affinity to cancer tissues because some of them were shown to bind readily to transferrin molecules.6 The ruthenium-transferrin complex is thought to be carried to tumor cells through transferrin receptors which are abundantly expressed on the surface of highly proliferative cells such as cancer cells.In recent years, colleagues in Neuchâtel as well as others have developed a series of ruthenium-based organometallic compounds offering efficacy toward cancer cells and giving the possibility to be activated by light.7-21 However, in these systems, the mode of action, uptake and the biological processes remain poorly understood. As such, our aims in this project are to define cellular targets of the compounds and elucidate some of their mechanistic profiles by various NMR techniques.We postulate that the uptake by cells of ruthenium compounds is mediated after binding to extracellular proteins, such as the transferrin or albumin.22 It is also known that DNA and cellular proteins are standard targets for ruthenium drugs. Thus, the detoxifying enzyme GST-p, the lysosomal hydrolases, the ubiquitin pathway and mitochondrial respiratory chain are also involved.10,23-25 These possibilities will form the basis of our initial working hypotheses. On the long term our goals are to further improve the efficacy of these compounds by designing new structures based on the information acquired in the proposed research project.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Name Institute

Publications

Publication
Highly cytotoxic trithiophenolatodiruthenium complexes of the type [(eta(6)-p-MeC6H4Pr (i) )(2)Ru-2(SC6H4-p-X)(3)](+): synthesis, molecular structure, electrochemistry, cytotoxicity, and glutathione oxidation potential
Giannini F, Furrer J, Ibao AF, Suss-Fink G, Therrien B, Zava O, Baquie M, Dyson PJ, Stepnicka P (2012), Highly cytotoxic trithiophenolatodiruthenium complexes of the type [(eta(6)-p-MeC6H4Pr (i) )(2)Ru-2(SC6H4-p-X)(3)](+): synthesis, molecular structure, electrochemistry, cytotoxicity, and glutathione oxidation potential, in JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY, 17(6), 951-960.
Insights into the Mechanism of Action and Cellular Targets of Ruthenium Complexes from NMR Spectroscopy
Giannini F, Paul LEH, Furrer J (2012), Insights into the Mechanism of Action and Cellular Targets of Ruthenium Complexes from NMR Spectroscopy, in CHIMIA, 66(10), 775-780.
Efficient Oxidation of Cysteine and Glutathione Catalyzed by a Dinuclear Areneruthenium Trithiolato Anticancer Complex
Giannini F, Suss-Fink G, Furrer J (2011), Efficient Oxidation of Cysteine and Glutathione Catalyzed by a Dinuclear Areneruthenium Trithiolato Anticancer Complex, in INORGANIC CHEMISTRY, 50(21), 10552-10554.
Synthesis, Characterisation, and in vitro Anticancer Activity of Hexanuclear Thiolato-Bridged Arene Ruthenium Metalla-Prisms
Furrer M. A., Garci A., Denoyelle-di-Muro E., Trouillas P., Giannini F., Furrer J., Clavel C. M., Dyson P. J., Süss-Fink G., Therrien B., Synthesis, Characterisation, and in vitro Anticancer Activity of Hexanuclear Thiolato-Bridged Arene Ruthenium Metalla-Prisms, in Chem Eur J.
Synthesis, characterization and in vitro anticancer activity of highly cytotoxic trithiolato diruthenium complexes of the type [(η6-Me¬C6H4-Pri)2Ru2(μ2-SR1)2(μ2-SR2)]+ contai¬ning different thiolato b
Giannini F, Furrer J, Ibao A F, Süss-Fink G, Clavel C M, Dyson P J, Synthesis, characterization and in vitro anticancer activity of highly cytotoxic trithiolato diruthenium complexes of the type [(η6-Me¬C6H4-Pri)2Ru2(μ2-SR1)2(μ2-SR2)]+ contai¬ning different thiolato b, in J. Organomet Chem.

Collaboration

Group / person Country
Types of collaboration
Department of Inorganic Chemistry Czech Republic (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Conference "cancer research: is NMR ready for prime time?" Talk given at a conference "cancer research: is NMR ready for prime time?" 08.11.2012 Berne, Suisse, Switzerland Furrer Julien;
Fall Meeting of the SCS Poster ... 12.09.2012 Zürich - Switzerland, Switzerland Furrer Julien; Giannini Federico;
EUROBIC 11 Poster ... 12.09.2012 Granada, Espagne, Spain Furrer Julien; Giannini Federico;
1st Year Graduate Symposium 2012 Talk given at a conference ... 10.09.2012 Berne Suisse, Switzerland Furrer Julien; Giannini Federico;
ISBOMC'12 Talk given at a conference ... 08.07.2012 Toronto, Canada, Canada Giannini Federico;
Congrès, EUROMAR 2012 Poster ... 01.07.2012 Dublin, Ireland Furrer Julien;
GECOM-CONCOORD 2012 Talk given at a conference ... 03.06.2012 Métabief, France, France Giannini Federico;
Conférence "Magnetic Resonance Spectroscopy and Methodology Seminars" Talk given at a conference Arene ruthenium complexes: insights into their potential modes of action using NMR 21.12.2011 Berne, Switzerland Furrer Julien;
Fall Meeting of the SCS 2011 Poster ... 09.09.2011 Lausanne, Switzerland, Switzerland Giannini Federico; Furrer Julien;
CUSO Summer School 2011 Talk given at a conference ... 28.08.2011 Villard, Switzerland Giannini Federico;
Congrès, XIX EuCheMS Conference on Organometallic Chemistry Poster ... 03.07.2011 Toulouse, France Giannini Federico; Furrer Julien;


Associated projects

Number Title Start Funding scheme
173718 Ruthenium Complexes for the Treatment of Protozoan Diseases of Medical and Veterinary Importance 01.09.2017 Sinergia
139078 1.7 mm Micro-Probehead for small volume NMR Spectroscopic Investigations 01.03.2012 R'EQUIP
144420 Bridged Dinuclear Arene Ruthenium Complexes: Cellular Targets and Mechanistic Profiles Investigated by NMR 01.01.2013 Project funding (Div. I-III)

Abstract

Unless platinum drugs which are long known to be also toxic to normal tissues, ruthenium-based drugs possess several favorable chemical properties indicating that some of them may be strong candidates to supplant those platinum-based drugs.1 Currently, two ruthenium-based anticancer drugs, NAMI-A2 and KP10193 have successfully completed phase I clinical trials and have entered phase II. NAMI-A appeared to be effective against lung metastases, whereas KP1019 showed activity against colon carcinomas and their metastases.4 Thus, ruthenium-based complexes form a basis for rational anticancer drug design. Several studies have revealed that most arene ruthenium complexes bind covalently to DNA via the N atom of purines and cause cytoxicity by inhibiting cellular DNA synthesis.5 Moreover, ruthenium complexes have a strong affinity to cancer tissues because some of them were shown to bind readily to transferrin molecules.6 The ruthenium-transferrin complex is thought to be carried to tumor cells through transferrin receptors which are abundantly expressed on the surface of highly proliferative cells such as cancer cells.In recent years, colleagues in Neuchâtel as well as others have developed a series of ruthenium-based organometallic compounds offering efficacy toward cancer cells and giving the possibility to be activated by light.7-21 However, in these systems, the mode of action, uptake and the biological processes remain poorly understood. As such, our aims in this project are to define cellular targets of the compounds and elucidate some of their mechanistic profiles.We postulate that the uptake by cells of ruthenium compounds is mediated after binding to extracellular proteins, such as the transferrin or albumin.22 It is also known that DNA and cellular proteins are standard targets for ruthenium drugs. Thus, the detoxifying enzyme GST-?, the lysosomal hydrolases, the ubiquitin pathway and mitochondrial respiratory chain are also involved.10,23-25These possibilities will form the basis of our initial working hypotheses. On the long term our goals are to further improve the efficacy of these compounds by designing new structures based on the information acquired in the proposed research project.The success of this project requires a collaborative approach between the group of Julien Furrer, Georg Süss-Fink (UNINE), Paul J. Dyson (EPFL), and Karim Elbayed, Martial Piotto, Izzie Jacques Namer (University of Strasbourg and CHU Hautepierre). A PhD candidate is requested to perform over a two year period this research project at the UNINE and for several short stays at the University of Strasbourg.
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