Project

Back to overview

Rational design of organo-ruthenium anticancer compounds with novel modes of action

English title Rational design of organo-ruthenium anticancer compounds with novel modes of action
Applicant Dyson Paul
Number 125173
Funding scheme Project funding (Div. I-III)
Research institution Laboratoire de chimie organométallique et médicinale EPFL - SB - ISIC - LCOM
Institution of higher education EPF Lausanne - EPFL
Main discipline Inorganic Chemistry
Start/End 01.04.2009 - 31.03.2012
Approved amount 383'519.00
Show all

All Disciplines (2)

Discipline
Inorganic Chemistry
Physical Chemistry

Keywords (10)

Bioorganometallic chemistry; Organometallic chemistry; Computational chemistry; Metal-based drugs; Bioorganometallic; Metal pharmaceuticals; Metal-protein interactions; Drug delivery; Molecular modelling; Proteomics

Lay Summary (English)

Lead
Lay summary
In this project we are studying a very promising new type of anticancer drugs that show selective toxicity in secondary (metastatic) cancers. Effective drugs for these secondary cancers are very limited and with surgical removal of primary cancers being well developed it is these secondary cancers are largely responsible for death in cancer patients. These new drugs developed at the EPFL termed RAPTA compounds are based on ruthenium and show remarkably low toxicity, which could be due to the formation of interactions with transferrin, a protein present in the blood that usually delivers iron to cells. Since cancer cells grow rapidly they require high levels of iron and therefore have more receptors for transferrin on their surface. It is possible that RAPTA compounds mimic iron and bind to transferrin leading to selective accumulation in cancer cells. In this project we intend to test this hypothesis using chemical, biochemical, biophysical and theoretical methods. We also intend to study in detail the binding mechanisms of RAPTA compounds to other possible targets involved in their antimetastatic action. A successful outcome of this project will be a greater understand of the mode of delivery of the RAPTA drugs that should ultimately allow us to develop compounds that are superior to those currently available.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Anthracene-Tethered Ruthenium(II) Arene Complexes as Tools To Visualize the Cellular Localization of Putative Organometallic Anticancer Compounds
Nazarov AA, Risse J, Ang WH, Schmitt F, Zava O, Ruggi A, Groessl M, Scopelitti R, Juillerat-Jeanneret L, Hartinger CG, Dyson PJ (2012), Anthracene-Tethered Ruthenium(II) Arene Complexes as Tools To Visualize the Cellular Localization of Putative Organometallic Anticancer Compounds, in INORGANIC CHEMISTRY, 51(6), 3633-3639.
Studies of glutathione transferase P1-1 bound to a platinum(IV)-based anticancer compound reveal the molecular basis of its activation.
Parker Lorien J, Italiano Louis C, Morton Craig J, Hancock Nancy C, Ascher David B, Aitken Jade B, Harris Hugh H, Campomanes Pablo, Rothlisberger Ursula, De Luca Anastasia, Lo Bello Mario, Ang Wee Han, Dyson Paul J, Parker Michael W (2011), Studies of glutathione transferase P1-1 bound to a platinum(IV)-based anticancer compound reveal the molecular basis of its activation., in Chemistry (Weinheim an der Bergstrasse, Germany), 17(28), 7806-16.
Organometallic Ruthenium(II) Arene Compounds with Antiangiogenic Activity
Nowak-Sliwinska P, van Beijnum JR, Casini A, Nazarov AA, Wagnieres G, van den Bergh H, Dyson PJ, Griffioen AW (2011), Organometallic Ruthenium(II) Arene Compounds with Antiangiogenic Activity, in JOURNAL OF MEDICINAL CHEMISTRY, 54(11), 3895-3902.
Adding diversity to ruthenium(II)-arene anticancer (RAPTA) compounds via click chemistry: The influence of hydrophobic chains
Renfrew AK, Juillerat-Jeanneret L, Dyson PJ (2011), Adding diversity to ruthenium(II)-arene anticancer (RAPTA) compounds via click chemistry: The influence of hydrophobic chains, in JOURNAL OF ORGANOMETALLIC CHEMISTRY, 696(3), 772-779.
Synthesis and characterisation of the water soluble bis-phosphine complex [Ru(eta(6)-cymene)(PPh2(o-C6H4O)-kappa(2)-P,O)(pta)](+) and an investigation of its cytotoxic effects
Renfrew AK, Egger AE, Scopelliti R, Hartinger CG, Dyson PJ (2010), Synthesis and characterisation of the water soluble bis-phosphine complex [Ru(eta(6)-cymene)(PPh2(o-C6H4O)-kappa(2)-P,O)(pta)](+) and an investigation of its cytotoxic effects, in COMPTES RENDUS CHIMIE, 13(8-9), 1144-1150.
Metabolization of [Ru(eta(6)-C (6)H (5)CF (3))(pta)Cl (2)]: a cytotoxic RAPTA-type complex with a strongly electron withdrawing arene ligand.
Egger Alexander E, Hartinger Christian G, Renfrew Anna K, Dyson Paul J (2010), Metabolization of [Ru(eta(6)-C (6)H (5)CF (3))(pta)Cl (2)]: a cytotoxic RAPTA-type complex with a strongly electron withdrawing arene ligand., in Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorga, 15(6), 919-27.
Rationalization of the inhibition activity of structurally related organometallic compounds against the drug target cathepsin B by DFT
Casini A, Edafe F, Erlandsson M, Gonsalvi L, Ciancetta A, Re N, Ienco A, Messori L, Peruzzini M, Dyson PJ (2010), Rationalization of the inhibition activity of structurally related organometallic compounds against the drug target cathepsin B by DFT, in DALTON TRANSACTIONS, 39(23), 5556-5563.
Use of perfluorinated phosphines to provide thermomorphic anticancer complexes for heat-based tumor targeting.
Renfrew Anna K, Scopelliti Rosario, Dyson Paul J (2010), Use of perfluorinated phosphines to provide thermomorphic anticancer complexes for heat-based tumor targeting., in Inorganic chemistry, 49(5), 2239-46.
Tuning the Efficacy of Ruthenium(II)-Arene (RAPTA) Antitumor Compounds with Fluorinated Arene Ligands
Renfrew AK, Phillips AD, Tapavicza E, Scopelliti R, Rothlisberger U, Dyson PJ (2009), Tuning the Efficacy of Ruthenium(II)-Arene (RAPTA) Antitumor Compounds with Fluorinated Arene Ligands, in ORGANOMETALLICS, 28(17), 5061-5071.
Reactivity of an antimetastatic organometallic ruthenium compound with metallothionein-2: relevance to the mechanism of action
Dyson Paul (2009), Reactivity of an antimetastatic organometallic ruthenium compound with metallothionein-2: relevance to the mechanism of action, in METALLOMICS , 1(5), 434-441.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Seminar 01.01.2012 Florence
XIX EuCheMS Conference on Organometallic Chemistry 01.07.2011 Toulouse
European Symposium on Experimental Metallodrugs 01.03.2011 Paris
Symposium on New Frontiers in Organic Synthesis XXV 01.11.2010 Milan
Seminar 01.10.2010 Vienna
5th International Symposium on Bioorganometallic Chemistry 01.07.2010 Bochum
Seminar 01.05.2010 Cambridge
Biomet9, 9th workshop on pharmaco-bio-metallics 01.11.2009 Sienna
Camerino summer school on organometallic chemistry, part II 15.09.2009 Camerino
Camerino summer school on organometallic chemistry, part I 01.09.2009 Camerino
Seminar, CERM Magnetic Resonance Center 01.06.2009 Florence
STRATEGIES FOR PRECLINICAL SELECTION OF METALBASED DRUGS FOR CANCER THERAPY 01.05.2009 Trieste


Awards

Title Year
Centennial Luigi Sacconi Medal 2011 2011

Associated projects

Number Title Start Funding scheme
116374 Rational design of organo-ruthenium anticancer compounds with novel modes of action 01.04.2007 Project funding (Div. I-III)
130647 An Integrated Approach to Study the Molecular Mechanisms of Ruthenium-Based Antitumour Agents (D-A-CH/LAV) 01.01.2011 Project funding (special)
140865 Rational design of organo-ruthenium anticancer compounds with novel modes of action 01.04.2012 Project funding (Div. I-III)
128901 Understanding the Mechanism of Action of Anticancer Organometallic Ruthenium(II) Compounds 01.03.2010 International short research visits
128752 Renewal of Central Computational Equipment 01.12.2009 R'EQUIP
116374 Rational design of organo-ruthenium anticancer compounds with novel modes of action 01.04.2007 Project funding (Div. I-III)

Abstract

In the last few years two ruthenium drugs have entered clinic trials generating considerable activity in the medicinal properties of ruthenium compounds, one of which has just started a phase II study in the UK. These drugs are effective against primary tumours and metastasis, for which cisplatin and other related drugs are ineffective. The ruthenium drugs also show remarkably low toxicity which contrasts with many other drugs, notably cisplatin. We describe an project that is concerned with the medicinal properties of organo-ruthenium compounds, a continuation of research already being undertaken at the EPFL, in a collaboration between the research groups of Dyson and Röthlisberger. A series of highly promising ruthenium(II)-arene (RAPTA) anticancer compounds which show selective toxicity in metastatic cancers is under investigation: two lead compounds have already been selected for a complete preclinical study with the aim of phasing one of them into clinical trials. This project is concerned with studying this class of compounds using chemical, biochemical, biophysical and theoretical methods. In particular we intend to study the interaction of the lead compounds with extracellular and intracellular protein targets. A number of studies have demonstrated the potential of transferrin (Tf) as a carrier protein for site-specific drug delivery and also for developing new therapeutic agents for a broad spectrum of diseases in the future. The fact that serum Tf is only about 30% saturated with iron, provides it with a potential capacity for binding to other metal ions that enter the body and preliminary data shows that RAPTA compounds bind to Tf, but it is not yet clear how and where they bind. Thus, we intend to study Tf-RAPTA interactions in detail.RAPTA complexes will be screened against intracellular proteins that represent “true” pharmacological targets for metal-based compounds. Among these possible families of target proteins are the proteinases cathepsins (in particular those isoforms that are crucial in certain types of cancer, such as cathepsin B), strictly linked to the processes of invasion and metastasis, and the thioredoxin reductases, selenoenzymes principally involved in the redox metabolism present in the cytosol and in the mitochondria. In addition, we will consider other enzymes relevant to cancer, such as kinases and zinc-finger containing proteins, that have been shown to be involved in the mechanism of pharmacological action of metal-based drugs. With an increased understanding of drug action we hope to be able to develop more effective compounds.
-