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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 140865
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 01.04.2012 - 30.09.2014
Approved amount 279'943.00
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Keywords (4)

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, like other ruthenium based compounds that are currently undergoing clinical trials. The exact mechanism by which these promising ruthenium antitumor compounds work remains unknown and in this project we intend to study their mode of action using chemical, biochemical, biophysical and theoretical methods. We intend to delineate the relevant targets and study in detail the binding mechanisms of the RAPTA compounds to them. A successful outcome of this project will be a greater understanding of the mechanism of action of the RAPTA drugs at a molecular level 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
Discovery of a highly tumor-selective organometallic ruthenium(II)-arene complex
Clavel Catherine M., Pǎunescu Emilia, Nowak-Sliwinska Patrycja, Griffioen Arjan W., Scopelliti Rosario, Dyson Paul J. (2014), Discovery of a highly tumor-selective organometallic ruthenium(II)-arene complex, in Journal of Medicinal Chemistry, 57(8), 3546-3558.
Ligand substitutions between ruthenium-cymene compounds can control protein versus DNA targeting and anticancer activity
Adhireksan Zenita, Davey Gabriela E., Campomanes Pablo, Groessl Michael, Clavel Catherine M., Yu Haojie, Nazarov Alexey A., Yeo Charmian Hui Fang, Ang Weehan, Dröge Peter, Röthlisberger Ursula, Dyson Paul J., Davey Curt Alexander (2014), Ligand substitutions between ruthenium-cymene compounds can control protein versus DNA targeting and anticancer activity, in Nature Communications, 5, 3462.
Selenoquinones stabilized by ruthenium(II) arene complexes: Synthesis, structure, and cytotoxicity
Dubarle-Offner Julien, Clavel Catherine M., Gontard Geoffrey, Dyson Paul J., Amouri Hani El (2014), Selenoquinones stabilized by ruthenium(II) arene complexes: Synthesis, structure, and cytotoxicity, in Chemistry - A European Journal, 20(19), 5795-5801.
Study of the Redox Properties of Singlet and Triplet Tris(2,2 '-bipyridine)ruthenium(II) ([Ru(bpy)(3)](2+)) in Aqueous Solution by Full Quantum and Mixed Quantum/Classical Molecular Dynamics Simulations
Diamantis Polydefkis, Gonthier Jerome Florian, Tavernelli Ivano, Rothlisberger Ursula (2014), Study of the Redox Properties of Singlet and Triplet Tris(2,2 '-bipyridine)ruthenium(II) ([Ru(bpy)(3)](2+)) in Aqueous Solution by Full Quantum and Mixed Quantum/Classical Molecular Dynamics Simulations, in JOURNAL OF PHYSICAL CHEMISTRY B, 118(14), 3950-3959.
Thermoresponsive organometallic arene ruthenium complexes for tumour targeting
Clavel Catherine M., Pǎunescu Emilia, Nowak-Sliwinska Patrycja, Dyson Paul J. (2014), Thermoresponsive organometallic arene ruthenium complexes for tumour targeting, in Chemical Science, 5(3), 1097-1101.
Cytotoxicity of Ruthenium-Arene Complexes Containing beta-Ketoamine Ligands
Pettinari Riccardo, Pettinari Claudio, Marchetti Fabio, Cavel Catherine M., Scopelliti Rosario, Dyson Paul J. (2013), Cytotoxicity of Ruthenium-Arene Complexes Containing beta-Ketoamine Ligands, in ORGANOMETALLICS, 32(1), 309-316.
Ruthenium(II) arene PTA (RAPTA) complexes: impact of enantiomerically pure chiral ligands
Kilpin Kelly J., Cammack Shona M., Clavel Catherine M., Dyson Paul J. (2013), Ruthenium(II) arene PTA (RAPTA) complexes: impact of enantiomerically pure chiral ligands, in DALTON TRANSACTIONS, 42(6), 2008-2014.
Synthesis, Characterisation and In Vitro Anticancer Activity of Hexanuclear Thiolato-Bridged Arene Ruthenium Metalla-Prisms
Furrer Mona A., Garci Amine, Denoyelle-Di-Muro Emmanuel, Trouillas Patrick, Giannini Federico, Furrer Julien, Clavel Catherine M., Dyson Paul J., Suess-Fink Georg, Therrien Bruno (2013), Synthesis, Characterisation and In Vitro Anticancer Activity of Hexanuclear Thiolato-Bridged Arene Ruthenium Metalla-Prisms, in CHEMISTRY-A EUROPEAN JOURNAL, 19(9), 3198-3203.
The influence of RAPTA moieties on the antiproliferative activity of peripheral-functionalised poly(salicylaldiminato) metallodendrimers
Govender Preshendren, Sudding Lara C., Clavel Catherine M., Dyson Paul J., Therrien Bruno, Smith Gregory S. (2013), The influence of RAPTA moieties on the antiproliferative activity of peripheral-functionalised poly(salicylaldiminato) metallodendrimers, in DALTON TRANSACTIONS, 42(4), 1267-1277.
Naphthalimide-Tagged Ruthenium-Arene Anticancer Complexes: Combining Coordination with Intercalation
Kilpin Kelly J., Clavel Catherine M., Edafe Fabio, Dyson Paul J. (2012), Naphthalimide-Tagged Ruthenium-Arene Anticancer Complexes: Combining Coordination with Intercalation, in ORGANOMETALLICS, 31(20), 7031-7039.

Collaboration

Group / person Country
Types of collaboration
Prof. Curt Davey, NTU Singapore (Asia)
- 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
9th Congress on Electronic Structures : Principles and Applications (ESPA) Poster . 01.07.2014 Badajoz, Spain Diamantis Polydefkis;
CPMD - Leipzig 2013 "Matter, life, light from ab initio molecular dynamics simulations Poster . 02.09.2013 Leipzig, Germany Diamantis Polydefkis;
6th International Symposium on Bioorganometallic Chemistry Talk given at a conference Thermoresponsive Organometallic Arena Ruthenium Derivatives for Tumor Targeting 08.07.2012 Toronto, Canada Clavel Catherine;


Awards

Title Year
EPFL Dimitris N. Chorafas Foundation Award 2014
EPFL Prize for Teaching Activities 2012
SCNAT/SCS Chemistry Travel Award 2012

Associated projects

Number Title Start Funding scheme
164011 Acquisition of the Central Computational Equipment for the Laboratory of Computational Chemistry and Biochemistry 01.10.2016 R'EQUIP
125173 Rational design of organo-ruthenium anticancer compounds with novel modes of action 01.04.2009 Project funding (Div. I-III)
157107 Modulation of the site specificity of binding of metal-based drugs to chromatin 01.10.2014 Project funding (Div. I-III)
133788 Metallomic Studies Using Electrospray Ionisation-Mass Spectrometry (ESI-MS) 01.12.2010 R'EQUIP

Abstract

Metastasis is the most deadly feature of cancer, accounting for greater than 90% of cancer-related mortality due to a lack of effective drugs. A few years ago we discovered a series of remarkably promising organo-ruthenium compounds that display selective activity against highly aggressive and metastatic tumors while apparently sparing healthy tissues. Based on the most recent studies (obtained in the last three years of this on-going project, and involving a number of vital national and international collaborations) we describe further relevant studies aimed at understanding the mode of action of these compounds in greater detail and in developing putative new derivatives with superior or targeted properties - notably a drug that we hope will show potential against invasive breast cancers. This current proposal builds on an existing and fruitful collaboration between the research groups of Paul Dyson (experimental approaches) and Ursula Röthlisberger (computational modelling) at the EPFL. Part of the research will be facilitated by key collaborations.The proposal is divided into three main sections with overlap and iterative processes connecting the various parts. Part 1 focuses on the critical role of transferrin as a carrier protein for site-specific drug delivery. Since serum transferrin (a protein that delivers iron to cells - cancer cells have a high requirement for iron with up to 10 times more transferrin receptors on their surface) is only about 30% saturated with iron, it has the capacity for binding to other metal ions that enter the body. Data show that RAPTA compounds have a lower efficacy in the absence of transferrin. Consequently, we intend to study the binding of RAPTA compounds to transferrin using a variety of biophysical tools and computational methods. The second part of the project extends on a recent crystallographic and bioanalytical study on the binding of a RAPTA compound to a nucleosome core particle. This study revealed that RAPTA-C binds exclusively to several sites of the histone protein core and not the DNA. In the next phase of this study we propose methods that should help us to learn how to modulate the site specificity of binding via control of steric and hydrophobic effects on the ring-substituents of the RAPTA structure. We also propose experiments that should help to unravel the connection between binding to the nucleosome (which appears to be highly relevant when compared to related data on cisplatin) and the pharmacological effects of RAPTA compounds. A detailed computational analysis of the obtained results is required to fully understand the binding preferences of RAPTA compounds. Additional experiments described in this part concerned with target identification are also planned.In the final part of the research program we describe the synthesis of new RAPTA compounds derivatized with doxorubicin, the latter being a front-line therapy for breast cancer, but marred by severe damage to healthy breast tissue. Combinations of doxorubicin and RAPTA-T were evaluated against both highly and poorly invasive human breast cancer cells, in comparison with non-tumoral human breast cells and it was found that RAPTA-T potentiated the doxorubicin-dependent inhibition of both protein and RNA synthesis, but not the DNA-damaging effects of doxorubicin and allowed doxorubicin to be applied in much lower doses with higher selectivity. Based on these data we have designed new RAPTA-doxorubicin hybrids and a series of relevant studies to evaluate the potential of these new compounds will be undertaken. Combined, it is hoped that these studies could lead to new therapies to treat tumors that have high mortality rates.
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