Ruthenium Organometallic Complexes
Lead Research Organisation:
University of Cambridge
Department Name: Chemistry
Abstract
The chemical fate of ruthenium organometallic complexes in a biological setting is an area of key research interest relevant to medicinal chemistry. This project will look to understand the mechanistic aspects of ruthenium complexes in a biological setting, focussing on two different biological applications.
1) Ru(II) arene complexes have been studied for their activity against cancer in vitro and in vivo. Through the optimisation and incorporation of a fluorinated ligand probe into Ru(II) arene complexes, the locations and modes of binding in a cell will be analysed, through 19F NMR, mass spectrometry an fluorescence microscopy. This information will lead to a more structured and less scattered approached to the design of ruthenium anti-cancer drugs.
2) Ruthenium complexes have well studied catalytic capabilities, for example, the use of Grubbs' catalyst in olefin metathesis. This project will look to introduce specific Ru organometallic catalysts into the active site of engineered enzymes. The key advantage of the enzyme is that it imparts high substrate specificity, and when combined with an organometallic catalyst the artificial metalloenzyme generated can have powerful catalytic properties. For example, Ru(II) arene complexes have shown catalytic activity in the C-H hydroxylation of an aromatic ketone, and these complexes will be attached to cysteine and/or histidine residues of the protease enzyme Subtilisin E.
1) Ru(II) arene complexes have been studied for their activity against cancer in vitro and in vivo. Through the optimisation and incorporation of a fluorinated ligand probe into Ru(II) arene complexes, the locations and modes of binding in a cell will be analysed, through 19F NMR, mass spectrometry an fluorescence microscopy. This information will lead to a more structured and less scattered approached to the design of ruthenium anti-cancer drugs.
2) Ruthenium complexes have well studied catalytic capabilities, for example, the use of Grubbs' catalyst in olefin metathesis. This project will look to introduce specific Ru organometallic catalysts into the active site of engineered enzymes. The key advantage of the enzyme is that it imparts high substrate specificity, and when combined with an organometallic catalyst the artificial metalloenzyme generated can have powerful catalytic properties. For example, Ru(II) arene complexes have shown catalytic activity in the C-H hydroxylation of an aromatic ketone, and these complexes will be attached to cysteine and/or histidine residues of the protease enzyme Subtilisin E.
Organisations
People |
ORCID iD |
| Paul Barker (Primary Supervisor) | |
| George Biggs (Student) |
Publications
Biggs G
(2020)
Unlocking the Full Evolutionary Potential of Artificial Metalloenzymes Through Direct Metal-Protein Coordination A review of recent advances for catalyst development
in Johnson Matthey Technology Review
Biggs GS
(2019)
Use of a fluorinated probe to quantitatively monitor amino acid binding preferences of ruthenium(ii) arene complexes.
in Dalton transactions (Cambridge, England : 2003)
Biggs GS
(2021)
Controlled Ligand Exchange Between Ruthenium Organometallic Cofactor Precursors and a Naïve Protein Scaffold Generates Artificial Metalloenzymes Catalysing Transfer Hydrogenation.
in Angewandte Chemie (International ed. in English)
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| EP/N509620/1 | 30/09/2016 | 29/09/2022 | |||
| 1800459 | Studentship | EP/N509620/1 | 30/09/2016 | 29/09/2020 | George Biggs |
| Description | This research has focussed around two biological applications of ruthenium organometallic complexes, their use as cytotoxic agents in the treatment of cancer and how they can be introduced into the active site of engineered enzymes to develop artificial metallo-enzymes. To address the first application, we have developed a spectroscopic approach, using NMR, to monitoring the speciation of ruthenium complexes in complex amino acid mixtures. This information will aid scientists in the design on new ruthenium anti-cancer drugs, which have currently failed to pass clinical trials, due to a lack of understanding of how and where they bind in a complex biological environment. To address the second application, we have explored the ligand exchange behaviour of different ruthenium complexes when they bind to different proteins. We have developed a method to control the metal coordination environment when binding to proteins. We have had particular success in coordinating ruthenium complexes to the four-helical bundle protein cytochrome b562 and gratifyingly we have observed catalytic activity in these ruthenium protein hybrids. Artificial metallo-enzymes, can have unique catalytic capabilities which can be very beneficial in synthetic biology. In particular we have seen success with these artificial metalloenzymes as catalyst for transfer hydrogenation which is a very relevant reaction in many industries including the pharmaceutical industry. This research has very much achieved the goals set out at the beginning of the award. |
| Exploitation Route | The findings from the project so far have led to the completion of a number of successful undergraduate research projects. Furthermore, this research has also formed the basis for a successful PhD application, which will explore the evolutionary potential of artificial metallo-enzymes generated by direct metal-protein coordination. |
| Sectors | Chemicals Healthcare Pharmaceuticals and Medical Biotechnology |