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Investigation of the interaction of transition metal based anticancer drugs with higher-order nucleic acids

Applicant Schürch Stefan
Number 149892
Funding scheme Project funding (Div. I-III)
Research institution Departement für Chemie, Biochemie und Pharmazie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Organic Chemistry
Start/End 01.03.2014 - 31.03.2017
Approved amount 198'600.00
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All Disciplines (2)

Discipline
Organic Chemistry
Biochemistry

Keywords (8)

rutenium complexes; higher-order nucleic acids; antitumor drugs; electrospray tandem mass spectrometry; double-stranded DNA; quadruplex DNA; cisplatin; transition metal complexes

Lay Summary (German)

Lead
Ziel des Projektes ist die Aufklärung der Wechselwirkung zwischen Übergangsmetall-basierenden Medikamenten und höher geordneten Nukleinsäure-Strukturen. Als analytische Methode wird die Tandem-Massenspektrometrie angewandt.
Lay summary

Nukleinsäuren spielen eine zentrale Rolle in zellulären Prozessen, sind sie doch für die Speicherung und Replikation der genetischen Information und deren Umsetzung in funktionelle Eiweissstoffe verantwortlich. Zudem üben Nukleinsäuren vielfältige regulatorische und katalytische Funktionen aus. Daher ist es nicht erstaunlich, dass Nukleinsäuren und besonders ihre biologisch relevanten höher geordneten Strukturen (z.B. doppelsträngige DNS) einen vielversprechenden Ansatzpunkt für die Behandlung von Krankheiten bilden.

Cisplatin ist der erste auf Übergangsmetallen basierende Wirkstoff, der bis heute erfolgreich in der Behandlung verschiedener Krebsarten angewendet wird. Leider ist diese Therapie mit schwerwiegenden Nebenwirkungen verbunden, was zur Entwicklung von Platin-basierenden Chemotherapeutika jüngerer Generation mit verbesserter Selektivität und Bioverfügbarkeit geführt hat.

Die Entwicklung neuer Therapeutika bedingt geeignete analytische Methoden, um die Wechselwirkung zwischen Nukleinsäuren und den Wirkstoffen aufzuklären. Die Tandem-Massenspektrometrie hat sich als ein geeignetes Hilfsmittel für diese Zwecke erwiesen, denn es lassen sich damit detaillierte Aussagen über die Selektivität, die Affinität und die Bindungsmotive der Wirkstoffe machen.

Dieses Forschungsprojekt zielt auf die Aufklärung der Wechselwirkung von Platin- und Ruthenium-basierenden Komplexen mit höher geordneten Nukleinsäure-Strukturen ab. Dadurch sollen mögliche Angriffspunkte der Medikamente identifiziert werden und Schlussfolgerungen über ihre  Wirkungsweise gezogen werden.

 

Direct link to Lay Summary Last update: 04.02.2014

Lay Summary (English)

Lead
The project aims at the elucidation of the interaction between transition metal-based drugs and higher-order nucleic acids, such as duplex- and quadruplex-DNA. Tandem mass spectrometry will be used as the main analytical tool.
Lay summary

Nucleic acids play a crucial role in cellular processes, as they are key elements responsible for storage and replication of the genetic information and its conversion into proteins. Moreover, they perform manifold regulatory and catalytic activities. Thus, it is not surprising that nucleic acids and especially their biologically relevant higher-order structures, such as duplexes and quadruplexes have gained increased attention as targets for the treatment of gene-related diseases. Among DNA-targeting drugs, cis-dichlorodiamineplatinum(II), known as cisplatin, was the first transition metal-based compound to be introduced as anti-tumor agent and it has been administered for the successful treatment of various types of cancer to this day. Unfortunately, the therapy provokes severe side effects, which triggered the search for alternative agents. Second and third generation platinum-based chemotherapeutics aim at increased selectivity of the drugs as well as improved delivery to their targets. While compounds based on substitute transition metals, namely ruthenium, are currently evaluated for their anti-proliferative activity against tumor cells as well, platinum-based agents remain unique in that their principal target in the cell is DNA.

With this background, the proposed research aims at the investigation of the interaction of platinum- and ruthenium-based complexes with higher-order nucleic acids in order to elucidate the selectivities, affinities, and binding motifs of the metallodrugs. Such information is required to assess potential nucleic acid targets of drug candidates, to draw conclusions about their structure-activity relationships, and to assist the future development of tailored, more selective-acting anticancer drugs. Though still in its infancy, tandem mass spectrometry of nucleic acid - drug adducts harbors a great potential in the field of gene-related diseases and results will broaden our understanding of the mode of action of transition metal-based therapeutics.

Direct link to Lay Summary Last update: 04.02.2014

Responsible applicant and co-applicants

Employees

Name Institute

Publications

Publication
Titanocene binding to oligonucleotides
Eberle Rahel P., Schürch Stefan (2018), Titanocene binding to oligonucleotides, in Journal of Inorganic Biochemistry, 184, 1-7.
Specific Interactions of Anti-tumor Metallocenes with Deoxydinucleoside Monophosphates
Eberle Rahel P., Hari Yvonne, Schürch Stefan (2017), Specific Interactions of Anti-tumor Metallocenes with Deoxydinucleoside Monophosphates, in J. Am. Soc. Mass Spectrom., 29(9), 1901-1909.
Transition Metal-based Anticancer Drugs Targeting Nucleic Acids: A Tandem Mass Spectrometric Investigation
Eberle Rahel P., Hari Yvonne, Schürch Stefan (2017), Transition Metal-based Anticancer Drugs Targeting Nucleic Acids: A Tandem Mass Spectrometric Investigation, in Chimia, (3), 120-123.
More Than Charged Base Loss — Revisiting the Fragmentation of Highly Charged Oligonucleotides
Nyakas Adrien, Eberle Rahel P., Stucki Silvan R., Schürch Stefan (2014), More Than Charged Base Loss — Revisiting the Fragmentation of Highly Charged Oligonucleotides, in Journal of The American Society for Mass Spectrometry, (7), 1155-1166.

Collaboration

Group / person Country
Types of collaboration
Prof. Dr. C. J. Leumann, University of Bern, Department of Chemistry and Biochemistry Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Dr. M. Fiedler, University of Bern, Institute for Clinical Chemistry Switzerland (Europe)
- Publication
- Research Infrastructure
PD Dr. J. Furrer, University of Bern, Department of Chemistry and Biochemistry Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Dr. B. Therrien, University of Neuchâtel, Institute of Chemistry Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Dr. R. Häner, University of Bern, Department of Chemistry and Biochemistry Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
CHanalysis 2018 Talk given at a conference Interaction of Antitumor Metallocenes with Nucleic Acids 12.04.2018 Beatenberg, Switzerland Eberle Rahel; Schürch Stefan;
Annual Meeting of the Swiss Group for Mass Spectrometry Poster The interaction of titanocene with DNA and RNA 25.10.2017 Beatenberg, Switzerland Eberle Rahel; Schürch Stefan;
SCS Fall Meeting Poster Titanocene and Nucleic Acids - Analysis of a Fruitful Liaison 21.08.2017 Bern, Switzerland Schürch Stefan; Eberle Rahel;
ASMS Conference on Mass Spectrometry and Allied Topics Poster The selective binding of titanocene to DNA and RNA 04.06.2017 Indianapolis, United States of America Eberle Rahel; Schürch Stefan;
Annual Meeting of the Swiss Group for Mass Spectrometry Poster Elucidation of the binding sites in antitumor metallocene - dinucleoside monophosphate adducts 27.10.2016 Beatenberg, Switzerland Eberle Rahel; Schürch Stefan;
SCS Fall Meeting Poster Tandem Mass Spectrometric Investigation of Titanocene and Cisplatin Adducts 15.09.2016 Zürich, Switzerland Schürch Stefan; Eberle Rahel;
ASMS Conference on Mass Spectrometry and Allied Topics Poster Interaction of Antitumor Metallocenes with Nucleic Acids 05.06.2016 San Antonio, TX, United States of America Schürch Stefan; Eberle Rahel;
Annual Meeting of the Swiss Group for Mass Spectrometry Poster Tandem Mass Spectrometric Analysis of Metallocene Adducts with Short Oligonucleotides 29.10.2015 Beatenberg, Switzerland Eberle Rahel; Schürch Stefan;
SCS Fall Meeting Poster Binding of Metallocenes to Short Oligonucleotides 04.09.2015 Lausanne, Switzerland Schürch Stefan; Eberle Rahel;
International Mass Spectrometry Conference (IMSC) Talk given at a conference Non-Standard Gas-Phase Fragmentation of Short, Highly Charged Oligonucleotides 24.08.2014 Geneva, Switzerland Schürch Stefan; Eberle Rahel;


Associated projects

Number Title Start Funding scheme
140628 Probing the interactions of organometallic compounds with nucleic acids by tandem mass spectrometry 01.04.2012 Project funding (Div. I-III)

Abstract

Quadruplexes are higher-order DNA structures consisting of stacked G-tetrads, which are formed by G-rich DNA sequences occurring in the chromosome ends. Quadruplexes were found to play a key role in various cellular processes, such as control of the telomere length and participation in gene regulation. Consequently, they also play a crucial role in the development of carcinomas. Thus, great efforts are taken to design and evaluate new drug candidates that target higher-order nucleic acids. Among the most prominent candidates are metallodrugs based on platinum and ruthenium. However, the modes of action and the structure-function relationships of many of these anticancer drugs are vaguely understood. With that background we propose to investigate the interaction of higher-order nucleic acids with newer-generation platinum drugs and potential chemotherapeutic agents based on other transition metal ions. Among the latter are ruthenium-based complexes with confirmed cytotoxic activity against tumor cell lines, and multinuclear compounds, which are able to cross-link nucleic acids, and thus, to interfere with the cellular replication machinery. Special attention will be given to cross-linking of bi- and monomolecular quadruplexes, as these are of increased biological relevance. The main goals of proposed research are the examination of the stoichiometries, affinities, selectivities, and binding modes of the different complexes to duplex DNA and in particular to quadruplex structures. Electrospray tandem mass spectrometry will be the main analytical tool. Thus, the specific mechanistic aspects of the gas-phase dissociation of the adducts have to be examined as well, since adduct formation may open up new fragmentation channels. Orthogonal analytical data will be provided by NMR, ion mobility spectrometry, and CD spectroscopy experiments (see detailed research plan). Support is requested for one graduate student for a period of three years and for a second graduate student for a period of one year (starting in the third year of the grant period). Such an arrangement would be highly beneficial, since it would ensure proper knowledge transfer and uninterrupted continuation of our research projects.
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