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Modulation of the site specificity of binding of metal-based drugs to chromatin

English title Modulation of the site specificity of binding of metal-based drugs to chromatin
Applicant Dyson Paul
Number 157107
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 01.10.2014 - 30.09.2018
Approved amount 621'289.00
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Keywords (5)

Chimie Bioinorganique; Chimie Bioorganométallique; Medicaments anti-cancer; Etudes mécanistiques; Etudes structurales

Lay Summary (French)

Lead
La chimiothérapie reste un moyen phare pour traiter le cancer, surtout lorsque les tumeurs sont métastasées et ne peuvent pas être enlevées par chirurgie. Une partie des médicaments utilisés en hôpital sont basés sur le platine et il est estimé qu’ils sont utilisés dans plus de la moitié des traitements à base de chimiothérapie. L’effet thérapeutique de ces composés est dû aux lésions provoquées par le médicament sur l’ADN. La géométrie des complexes de platine utilisés ne propose qu’une spécificité modérée sur la double hélice, et les adduits se forment préférentiellement avec le nucléotide guanine. D’autres composés basés sur différents métaux sont actuellement étudiés, et, les médicaments au ruthénium sont perçus comme un alternatif prometteur au platine. Certain composés au ruthénium montrent une activité spécifique contre certains types de cancers, ainsi qu’une toxicité et une excrétion favorable. Cependant, leur mécanisme d’action n’est pas bien compris.
Lay summary

Contenu et objectifs du travail de recherche 

 En s’inspirant d’études précédentes, nous avons l’intention de développer des nouveaux agents thérapeutiques, conçus grâce aux informations obtenues de données cristallographiques et computationnelles. Une approche « atome-à-cellule » sera utilisée, comprenant des études structurales (cristallographie) et mécanistiques (computationnelles). Basé sur cette étude, nous devrions établir de nouveaux concepts pour améliorer et mieux contrôler la liaison de l’agent thérapeutique à sa cible.

 

Contexte scientifique et social du projet de recherche

Ces nouvelles études devraient mener à une meilleure compréhension du mode d’action des médicaments anti-cancéreux au ruthénium, ainsi que de permettre de développer des agents thérapeutiques de qualité supérieure possédant une meilleure activité et sélectivité, ce qui devrait mener à moins d’effets secondaires lors des traitements.

Direct link to Lay Summary Last update: 13.10.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Conjugating Biotin to Ruthenium(II) Arene Units via Phosphine Ligand FunctionalizationConjugating Biotin to Ruthenium(II) Arene Units via Phosphine Ligand Functionalization
Biancalana Lorenzo, Gruchała Martyna, Batchelor Lucinda K., Błauż Andrzej, Monti Andrea, Pampaloni Guido, Rychlik Błażej, Dyson Paul J., Marchetti Fabio (2020), Conjugating Biotin to Ruthenium(II) Arene Units via Phosphine Ligand FunctionalizationConjugating Biotin to Ruthenium(II) Arene Units via Phosphine Ligand Functionalization, in European Journal of Inorganic Chemistry, 2020(11-12), 1061-1072.
Diiron Complexes with a Bridging Functionalized Allylidene Ligand: Synthesis, Structural Aspects, and Cytotoxicity
SchochSylvia, BatchelorLucinda K., FunaioliTiziana, CiancaleoniGianluca, ZacchiniStefano, BracciniSimona, ChielliniFederica, BiverTarita, PampaloniGuido, DysonPaul J., MarchettiFabio (2020), Diiron Complexes with a Bridging Functionalized Allylidene Ligand: Synthesis, Structural Aspects, and Cytotoxicity, in Organomettalics, 39, 361-373.
Piano Stool Aminoalkylidene‐Ferracyclopentenone Complexes from Bimetallic Precursors: Synthesis and Cytotoxicity Data
Rocco Dalila, Batchelor Lucinda K., Ferretti Eleonora, Zacchini Stefano, Pampaloni Guido, Dyson Paul J., Marchetti Fabio (2020), Piano Stool Aminoalkylidene‐Ferracyclopentenone Complexes from Bimetallic Precursors: Synthesis and Cytotoxicity Data, in ChemPlusChem, 85(1), 110-122.
Crosslinking Allosteric Sites on the Nucleosome
Batchelor Lucinda K., De Falco Louis, Erlach Thibaud, Sharma Deepti, Adhireksan Zenita, Roethlisberger Ursula, Davey Curt A., Dyson Paul J. (2019), Crosslinking Allosteric Sites on the Nucleosome, in Angewandte Chemie International Edition, 58(44), 15660-15664.
Anticancer Potential of Diiron Vinyliminium Complexes
Rocco Dalila, Batchelor Lucinda K., Agonigi Gabriele, Braccini Simona, Chiellini Federica, Schoch Silvia, Biver Tarita, Funaioli Tiziana, Zacchini Stefano, Biancalana Lorenzo, Ruggeri Marina, Pampaloni Guido, Dyson Paul J., Marchetti Fabio (2019), Anticancer Potential of Diiron Vinyliminium Complexes, in Chemistry – A European Journal, 25(65), 14801-14816.
Histidine Targeting Heterobimetallic Ruthenium(II)–Gold(I) Complexes
Batchelor Lucinda K., Ortiz Daniel, Dyson Paul J. (2019), Histidine Targeting Heterobimetallic Ruthenium(II)–Gold(I) Complexes, in Inorganic Chemistry, 58(4), 2501-2513.
α-Diimine homologues of cisplatin: synthesis, speciation in DMSO/water and cytotoxicity
Biancalana Lorenzo, Batchelor Lucinda K., Dyson Paul J., Zacchini Stefano, Schoch Silvia, Pampaloni Guido, Marchetti Fabio (2018), α-Diimine homologues of cisplatin: synthesis, speciation in DMSO/water and cytotoxicity, in New Journal of Chemistry, 42(21), 17453-17463.
α-Diimines as Versatile, Derivatizable Ligands in Ruthenium(II) p -Cymene Anticancer Complexes
Biancalana Lorenzo, Batchelor Lucinda K., Funaioli Tiziana, Zacchini Stefano, Bortoluzzi Marco, Pampaloni Guido, Dyson Paul J., Marchetti Fabio (2018), α-Diimines as Versatile, Derivatizable Ligands in Ruthenium(II) p -Cymene Anticancer Complexes, in Inorganic Chemistry, 57(11), 6669-6685.
Applying a Trojan Horse Strategy to Ruthenium Complexes in the Pursuit of Novel Antibacterial Agents
Laurent Quentin, Batchelor Lucinda K., Dyson Paul J. (2018), Applying a Trojan Horse Strategy to Ruthenium Complexes in the Pursuit of Novel Antibacterial Agents, in Organometallics, 37(6), 915-923.
Versatile coordination of acetazolamide to ruthenium( ii ) p -cymene complexes and preliminary cytotoxicity studies
Biancalana Lorenzo, Batchelor Lucinda K., Ciancaleoni Gianluca, Zacchini Stefano, Pampaloni Guido, Dyson Paul J., Marchetti Fabio (2018), Versatile coordination of acetazolamide to ruthenium( ii ) p -cymene complexes and preliminary cytotoxicity studies, in Dalton Transactions, 47(28), 9367-9384.
Nucleosome acidic patch-targeting binuclear ruthenium compounds induce aberrant chromatin condensation
Davey Gabriela E., Adhireksan Zenita, Ma Zhujun, Riedel Tina, Sharma Deepti, Padavattan Sivaraman, Rhodes Daniela, Ludwig Alexander, Sandin Sara, Murray Benjamin S., Dyson Paul J., Davey Curt A. (2017), Nucleosome acidic patch-targeting binuclear ruthenium compounds induce aberrant chromatin condensation, in Nature Communications, 8(1), 1575-1575.
Influence of the Linker Length on the Cytotoxicity of Homobinuclear Ruthenium(II) and Gold(I) Complexes
Batchelor Lucinda K., Păunescu Emilia, Soudani Mylène, Scopelliti Rosario, Dyson Paul J. (2017), Influence of the Linker Length on the Cytotoxicity of Homobinuclear Ruthenium(II) and Gold(I) Complexes, in Inorganic Chemistry, 56(16), 9617-9633.
Allosteric cross-talk in chromatin can mediate drug-drug synergy
Adhireksan Zenita, Palermo Giulia, Riedel Tina, Ma Zhujun, Muhammad Reyhan, Rothlisberger Ursula, Dyson Paul J., Davey Curt A. (2017), Allosteric cross-talk in chromatin can mediate drug-drug synergy, in Nature Communications, 8, 14860-14860.
A general strategy to add diversity to ruthenium arene complexes with bioactive organic compounds via a coordinated (4-hydroxyphenyl)diphenylphosphine ligand
Biancalana Lorenzo, Batchelor Lucinda K., De Palo Alice, Zacchini Stefano, Pampaloni Guido, Dyson Paul J., Marchetti Fabio (2017), A general strategy to add diversity to ruthenium arene complexes with bioactive organic compounds via a coordinated (4-hydroxyphenyl)diphenylphosphine ligand, in Dalton Transactions, 46(36), 12001-12004.

Collaboration

Group / person Country
Types of collaboration
Prof. Curt Davey, NTU Singapore (Asia)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Lecture University of Basel Individual talk The development of organometallic antitumor drugs based on ruthenium 23.11.2018 Basel, Switzerland Dyson Paul;
The Bonati Lecture at the XLIII National Congress of the Division of Inorganic Chemistry of the Italian Chemical Society Talk given at a conference The development of organometallic anticancer drugs based on ruthenium 10.09.2018 Camerino, Italy Dyson Paul;
SCS Fall Meeting 2018 Poster Bridging The Gap : Crosslinking Allosteric Sites on the Nucleosome 07.09.2018 EPFL, Switzerland Batchelor Lucinda Kate;
University of Edinburgh Individual talk The Development of Organometallic Ruthenium-based Anticancer Drugs 21.08.2018 Edinburgh, Great Britain and Northern Ireland Dyson Paul;
plenary lecture at the XXVIII International Conference on Organometallic Chemistry Talk given at a conference The development of organometallic anticancer drugs that operate via epigenetic mechanisms 16.07.2018 Florence, Italy Dyson Paul;
Frontiers and challenges of computing metals for biochemical, medical and technological applications Talk given at a conference Organometallic anticancer drugs that modulate the tumor microenvironment 11.07.2018 Paris, France Dyson Paul;
16th Swiss Snow Symposium 2018 (SSS'18) Talk given at a conference Bridging the Gap: Crosslinking Allosteric Sites on the NCP 26.01.2018 Saas-Fee, Switzerland Batchelor Lucinda Kate;
31st Seminar of the PhD program in Pharmaceutical Sciences of the University of Geneva Individual talk Chemistry in drug development 28.08.2017 Zermatt, Switzerland Dyson Paul;
Metallomics 2017: 6th International Symposium on Metallomics Talk given at a conference The influence of RAPTA-T on the tumor microenvironment 14.08.2017 Vienna, Austria Dyson Paul;
Chemistry Anniversary Lectureship 2016-17 Individual talk Organometallic Anticancer Drugs with Novel Modes of Action 24.10.2016 York, Great Britain and Northern Ireland Dyson Paul;
Auspherix pharmaceuticals Individual talk Organometallic pharmaceuticals 28.03.2016 Stevenage, Great Britain and Northern Ireland Dyson Paul;
RSC Bioinorganic Chemistry 2015 Prize lecture Individual talk The development of organometallic anticancer drugs based on ruthenium 19.10.2015 Newcastle, Hull and Loughborough, Great Britain and Northern Ireland Dyson Paul;


Awards

Title Year
Bioinorganic Award of the Royal Society of Chemistry 2015

Associated projects

Number Title Start Funding scheme
140865 Rational design of organo-ruthenium anticancer compounds with novel modes of action 01.04.2012 Project funding (Div. I-III)
164090 Request for an Electron Detection Camera 01.01.2016 R'EQUIP
185092 Next-Generation Multiscale Molecular Dynamics: Promoting Computational Chemistry with Artificial Intelligence 01.05.2019 Project funding (Div. I-III)

Abstract

En s’inspirant d’études précédentes, nous avons l’intention de développer des nouveaux agents thérapeutiques, conçus grâce aux informations obtenues de données cristallographiques et computationnelles. Une approche « atome-à-cellule » sera utilisée, comprenant des études structurales (cristallographie) et mécanistiques (computationnelles). Basé sur cette étude, nous devrions établir de nouveaux concepts pour améliorer et mieux contrôler la liaison de l’agent thérapeutique à sa cible.
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