Interaction of metal complexes with DNA and proteins: towards a new generation of therapeutic and imaging agents
Lead Research Organisation:
Imperial College London
Department Name: Chemistry
Abstract
The search for new chemicals that have therapeutic properties is a lengthy and costly process that continuously looks for chemical diversity. While organic compounds have been extensively studied in this context far less is known about the therapeutic properties of metal complexes. In spite of the great success of some metallo-pharmaceuticals such as cis-platin in cancer therapy, and gadolinium complexes in Magnetic Resonance Imaging (MRI), medicinal inorganic chemistry has received comparatively very little attention from the pharmaceutical industry and in general from the medicinal chemistry community. However, the structural and electronic versatility of metal centres provide a unique opportunity to explore chemical diversity for the rational design of drugs. Furthermore, metals often have attractive optical and magnetic properties that are ideally suited for the development of molecular probes for bio-imaging. The project herein presented aims at developing novel metal complexes as potential anticancer drugs. In particular, we will aim to develop complexes that can selectively interact with a specific type of DNA (named quadruplex DNA which in recent years has been increasingly associated with regulatory processes in the human genome and has emerged as a novel and distinctive target for the development of anticancer drugs). To realize the full therapeutic potential of the compounds developed, their interactions with proteins relevant to transport and delivery will be studied. Besides the potential therapeutic properties of the compounds developed (with the obvious implications to a range of beneficiaries) we will also aim to develop molecular probes that can be used to gain a better understanding of the interaction of small molecules and quadruplex DNA.Metal-containing compounds have been overlooked for a long time by the pharmaceutical industry and medicinal chemistry community. However, their distinctive structural and functional properties provide a unique opportunity for the development of new therapeutic agents and imaging tools. The vision of this project is to demonstrate that metal complexes that interact with quadruplex DNA, can be excellent candidates for the development of anticancer drugs and also unique probes for bio-imaging.
People |
ORCID iD |
Ramon Vilar Compte (Principal Investigator) |
Publications
Surman AJ
(2011)
Targeting of anionic membrane species by lanthanide(III) complexes: towards improved MRI contrast agents for apoptosis.
in Chemical communications (Cambridge, England)
Von Grebe P
(2013)
A conformationally flexible dinuclear Pt(II) complex with differential behavior of its two states toward quadruplex DNA.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Zhou CQ
(2017)
Dinickel-Salphen Complexes as Binders of Human Telomeric Dimeric G-Quadruplexes.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Description | In this project, we have developed a series of molecular probes to understand the role that non-canonical DNA structures play in live cells. The most important finding, was a fluorescent molecule that changes its optical properties when bound to different structures of DNA. In particular, it has a very long fluorescence when it binds to a quadruply-stranded DNA (known as G-quadruplexes) as compared to when it binds to the canonical DNA double helix. This has allowed us to visualize for the first time, the presence of quadruplex DNA in cells. This is important since this type of structure has been associated to a number of key biological processes (e.g. how cells regulate the formation of certain proteins or how cells divide). More about this story can be found at: http://www.nature.com/ncomms/2015/150909/ncomms9178/abs/ncomms9178.html (published paper) as well as in the following link: http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/newssummary/news_8-9-2015-15-16-31 |
Exploitation Route | Yes. The probes we have developed will be very useful to biologists interested in understanding the roles non-canonical DNA structures play in vivo. |
Sectors | Chemicals,Healthcare |
URL | http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/newssummary/news_8-9-2015-15-16-31 |
Description | The new probes we have developed have already been used by other research groups to monitor the biology of quadruplexes. This has so far been at a non-commercial level but there might be scope to explore commericalization of some of the probes we develop. |
First Year Of Impact | 2016 |
Sector | Chemicals,Healthcare |
Description | BBSRC Development Fund |
Amount | £140,181 (GBP) |
Funding ID | BB/P026109/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 11/2017 |
End | 11/2018 |
Description | Excellence Fund for Frontiers Research |
Amount | £250,000 (GBP) |
Organisation | Imperial College London |
Sector | Academic/University |
Country | United Kingdom |
Start | 04/2017 |
End | 04/2019 |
Description | Research Project from BHF |
Amount | £181,653 (GBP) |
Funding ID | PG/11/81/29130 |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 02/2012 |
End | 01/2015 |
Description | Structural ellucidation of the interaction between small molecules and G-quadruplex DNA |
Organisation | National Institute of Chemistry, Slovenia |
Country | Slovenia |
Sector | Academic/University |
PI Contribution | This collaboration allowed us to establish the exact binding mode of one of our DNA optical probes with G-quadruplex DNA. We synthesized the new optical probe and demonstrated it acts as an excellent optical probe. |
Collaborator Contribution | The collaborators at the NMR centre in Slovenia, were able to determine the NMR structure of the probe-DNA complex. This has provided important insights into the binding mode of the probe allowing us to rationally design new probes. |
Impact | Joint high-impact publication: A. Kotar, B. Wang, A. Shivalingam, J. Gonzalez-Garcia, R. Vilar, J. Plavec, "NMR Structure of a Triangulenium based Long-lived Fluorescence Probe Bound to G-quadruplex", Angew. Chem. Int. Ed. 2016, 55, 12508-12511. (DOI: 10.1002/anie.201606877) |
Start Year | 2015 |
Description | Bioinorganic Chemistry Conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited keynote lecture at the 5ht Latin American Meeting on Biological Inorganic Chemistry |
Year(s) Of Engagement Activity | 2016 |
URL | http://www.labic2016.cinvestav.mx/ |
Description | Delivered a talk to secondary school science teachers |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Delivered a talk on 'Metals in Medicine' to secondary school teachers. The talk was followed by a Q&A session with the teachers. This activity was organised by The Prince's Teaching Institute, a charity set up to re-inspire and reinvigorate secondary school teachers by providing them with high quality subject-based professional development. |
Year(s) Of Engagement Activity | 2016 |
Description | IC3EM Conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Delivered a Keynote lecture on imaging G-quadruplex DNA with small molecule probes |
Year(s) Of Engagement Activity | 2014 |
Description | ISABIC12 Conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Delivered an invited lecture at this international conference which is attended by leading experts in the field as well as PG students carrying out their research in bioinorganic chemistry |
Year(s) Of Engagement Activity | 2013 |
Description | ISABIC13 Conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Delivered a lecture at this international conference - attended by leading experts in applied bioinorganic/medicinal inorganic chemistry (inlcuding PG students working in this area) |
Year(s) Of Engagement Activity | 2015 |
Description | Invited Lecture |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | I delivered an invited lecture at the 14th European Biological Inorganic Chemistry Conference (EUROBIC). The lecture was attended by ca. 80 colleagues/postgraduate students |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.birmingham.ac.uk/facilities/mds-cpd/conferences/eurobic/index.aspx |
Description | Invited lecture - Organic photochemistry meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited lecture at the University of Pavia - One-day meeting (Organic photochemistry) |
Year(s) Of Engagement Activity | 2017 |
Description | Invited lecture at EuroBIC-12 conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | Talk sparked questions and fruitful discussion afterwards Attending the meeting and giving the talk generated a new international research collaboration |
Year(s) Of Engagement Activity | 2014 |
URL | http://www.imotif.org/eurobic/ |
Description | Invited speaker at ICIQ 10th Anniversary Symposium |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | Talk stimulated discussion Talk stimulated fruitful discussion |
Year(s) Of Engagement Activity | 2014 |
URL | http://10thanniversarysymposium.iciq.es/ |
Description | Lecture at 2nd International Symposium on Bioinorganic Chemistry |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Type Of Presentation | keynote/invited speaker |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Talk sparked questions and discussion afterwards |
Year(s) Of Engagement Activity | 2009 |
Description | Lecture at 5th EuCheMS Conference on Nitrogen Ligands |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Type Of Presentation | keynote/invited speaker |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Talk sparked questions and discussion afterwards Several new research collaborations were established as part of this meeting |
Year(s) Of Engagement Activity | 2011 |
Description | Lecture at ICCC40 conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Type Of Presentation | keynote/invited speaker |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Keynote lecture at the most important International Coordination Chemistry Conference. Talk sparked questions and discussion afterwards Talk sparked questions and discussion afterwards |
Year(s) Of Engagement Activity | 2012 |
URL | http://iccc40.pacifico-meetings.com/ |
Description | Lecture at International Conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Lecture at the 6th International Meeting on Quadruplex Nucleic Acids |
Year(s) Of Engagement Activity | 2017 |
Description | Lecture for the Prince's Teaching Institute |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Talk sparked questions from audience related to ways of improving science teaching at secondary schools |
Year(s) Of Engagement Activity | 2014 |
Description | Lecture given at Novartis |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Gave a lecture to scientist from Novartis research center. This was followed by several meetings and discussion of possible collaborative research. |
Year(s) Of Engagement Activity | 2013 |
Description | Plenary Lecture - Conference Mexican Chemical Society |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Plenary lecture at the 52nd Conference of the Mexican Chemical Society |
Year(s) Of Engagement Activity | 2017 |