Apply for a funded PhD position

Background

There is a lot more to DNA than the Watson-Crick double helix. As a flexible polymer, it folds in different ways adopting many different secondary structures. Much less is known about these structures – how and when they form, what they do and how their structure relates to their role. Even so, such “alternative” structures have been linked to switch on/off of genes, and thus to genetic diseases: understanding them is vital to development of new therapies and diagnostics. i-Motif (iM) DNA – the focus of this project – is an exciting current topic as its existence in organisms was only proven in 2018. Consequently, while iM containing sequences have been linked to diabetes and cancer, little is known about their biological structure/function relationships, and research is held back by a lack of effective detection methods that can be applied to live cells and organisms.

This project, aimed at developing metal-based small molecule iM probes compatible with live cells, tissues and organisms, is led by Dr John Fielden, who joins the Chemistry Department at the University of Lancaster at the end of January 2023. Research in the Fielden Group is focused on the synthesis, photophysical and electrochemical properties of new molecular inorganic compounds, and their application in fields ranging from non-linear optics, to biological imaging and detection.

Project description

A 3.5 year Faculty of Science funded PhD position is available at Lancaster University, focused on design, synthesis and testing of new ruthenium-based small molecule probes for i-Motif DNA (iM). The project is in collaboration with Dr. Zoë Waller (School of Pharmacy, University College London), and follows up our recent discovery of a ruthenium complex that can, in vitro, detect iM in the presence of other DNA forms (J. Am. Chem. Soc. 2020, 142, 13856) through observation of a phosphorescence lifetime increase.

Existing means of detecting iM are only compatible with fixed, dead cells, whereas ruthenium complexes have demonstrated uptake, and tolerance by live cells and organisms. Thus, our discovery has potential to enable detection and study of the role of iM in living systems, and ultimately inform development of diagnostics and treatments for iM-linked genetic diseases. The studentship will take key steps towards this goal by synthesing new analogues of our lead compound, designed to have stronger and more specific responses to iM. It will also improve our understanding of the phosphorescence switch-on, and begin the work of translating the research from the test tube to cells.

The project will provide training in ligand and metal complex design and synthesis, including handling of air and moisture sensitive reagents (Schlenk technique), and a full range of molecular characterisation techniques (NMR & IR spectroscopy, mass spectrometry, X-ray crystallography). You will learn photophysical characterisation methods (UV-vis, fluorescence/phosphorescence, circular dichroism) and their application to biophysical chemistry, and be involved in the first studies of these compounds in live cells. Biophysical and biological work will be conducted in collaboration with the Waller group, and is expected to include short visits or secondments to UCL.

Requirements

Applicants will hold, or expect to receive, a 1st class or 2:1 UK Masters-level or BSc degree (or equivalent) in Chemistry, or a closely related discipline and possess theoretical and practical skills commensurate with a science-based undergraduate degree programme. Candidates with a 2:2 may be considered if they can demonstrate excellent research skills in their application and references.

The successful candidate will combine a strong interest in synthetic coordination and organometallic chemistry with curiosity about the interaction of small molecules with biological systems, and the willingness to learn and apply multiple photophysical and biophysical techniques. They will also have enthusiasm for work in a laboratory environment, a collaborative attitude, and excellent written and oral communication skills in English.

How to apply (Please read carefully)

Dr John Fielden encourages informal email enquiries before submitting an application (j.fielden@lancaster.ac.uk). Please note that we cannot receive applications by email as they must be processed centrally.

Applications should be made via Lancaster University’s online application system

Please indicate on your application that you are applying for this funded PhD project by declaring the title of the advertisement where prompted. You may use the project description as your research proposal to apply for this studentship.

Funding Details

The studentship will cover fees at the UK rate plus the standard maintenance stipend.

It may also fully or partially contribute to the fees and stipend of a self-funded international candidate, though it is advised that you enquire regarding this before applying.

Deadline: 20^th January 2022. Shortlisted candidates will be interviewed in early February.

Background

Dr Muñoz will be joining the Chemistry Department at the University of Lancaster at the end of January 2023. Research in Dr Muñoz’s research group focuses on synthetic organic/organometallic chemistry with particular interest in the discovery and development of new organic and organometallic reactions, the use of physical-organic-inorganic chemistry to study mechanisms, and the application of the knowledge acquire to the synthesis of small organic and organometallic molecules with potential biological activity.

There is a constant demand for original, more potent drugs to target new and old diseases. Natural products remain a good source of pharmaceuticals, but their availability is limited in many cases. Consequently, innovative drug design, investigations of SAR (structure activity relationships) to generate libraries of potential lead compounds is of crucial importance and one of the frontier challenges of chemistry in the 21^st century. The development of metal complexes as therapeutic agents has attracted much attention in recent years, as coordination chemistry gives access to 3D structures of different shapes, with advantages over classic organic compounds. Although platinum-complexes have been extensively studied, and cis-platin is still one of the most used anticancer metallodrugs, there are still issues with toxicity and selectivity. Gold-complexes have appeared as strong alternatives, and they have been shown to act through several biochemical mechanisms, including interaction with DNA.

In medicinal organometallic chemistry, the design of the ligand is crucial to control the properties, stability, and selectivity of the metal complexes. In the last few years the Muñoz group has pioneered the synthesis of novel robust gold carbenes stabilised by a b-pyridine nitrogen, formed by nucleophilic cyclisation of bispyridyl allenes activated by the gold complexes. These carbenes not only are active catalysts of organic reactions (Dalton Trans., 2020, 49, 4034), but also show promising antifungal (JACS Au, 2022, 2, 10, 2277), antimicrobial and anticancer activities, and specific interactions with non-canonical forms of DNA (e.g. i-motif, unpublished), opening new avenues for research into gold metallodrugs with alternative mechanisms of action.

Project description

A 3.5 year Faculty of Science funded PhD position is available in Lancaster University in the area of organometallic synthesis, starting in October 2023.

The main objective of this PhD project is to develop a library of gold-carbene complexes b-stabilised by N-heterocyclic ligands, one of the most privileged structures among pharmaceutical drugs in the market, and to investigate their catalytic and also biological activity, in the quest for novel metallodrugs that will overcome issues with current organic and organometallic leads (e.g. toxicity, potency, selectivity). Extension of the pyridine-containing complexes to other nitrogen containing heterocycles (quinolines, pyrimidines, isoquinolines) and study of the factors that control and contribute to the biological activity as antifungal, antimicrobial (with CO-ADD) and anticancer activity, and their specific interaction with different forms of DNA, will be studied experimentally and computationally in the group and through collaborators (with Dr. Zoë Waller, School of Pharmacy, University College London). The project will also aim to expand the application of the gold carbene complexes in asymmetric catalysis, either by synthesising the chiral complexes from enantiomerically enriched allenes, by chiral resolution of the racemic gold carbene complexes, or by exploiting the selective interaction of the racemic complexes with inherently chiral DNA structures towards novel DNA-asymmetric organometallic catalysis.

The project combines classic organic chemistry for the synthesis of starting materials, with inorganic synthesis of gold complexes, and organometallic, including asymmetric, catalysis. Training objectives within the project are to improve existing skills in synthetic laboratory techniques and characterisation of organic and inorganic compounds (NMR, MS, X-Ray), as well as learning new techniques in organometallic (Schlenk) and asymmetric (HPLC) catalysis, but also in physical organic (e.g. isotopic labelling, reaction monitoring) and medicinal chemistry, including biophysical techniques for the studies of the interaction of the complexes with DNA (e.g. FRET, FID and CD, with collaborators). The student will be encouraged to develop their own ideas within the research project and to communicate their results in weekly meetings with the supervisor. The student will be expected to participate in preparation of papers for publication and present their work in departmental, national and international meetings. The student will join fortnightly group meetings and additional departmental problem sessions. These occasions provide an excellent opportunity for teaching and discussing chemistry and developing research ideas for the future. The student will have access to a range of graduate skills training courses run by Lancaster University (e.g. project management, improved presentations), and to peer mentoring.

Requirements

Applicants will hold, or expect to receive, a 1st class or 2:1 UK Masters-level or BSc degree (or equivalent) in Chemistry, or related discipline and possess theoretical and practical skills commensurate with a science-based undergraduate degree programme. Candidates with a 2:2 may be considered if they can demonstrate excellent research skills in their application and references.

The successful candidate will demonstrate a strong background in synthetic organic-organometallic chemistry and interest in physical organic and biophysical chemistry, enthusiasm to work in a laboratory environment, willingness to learn, a collaborative attitude, and will possess good written and oral communication skills.

How to apply (Please read carefully)

Dr M. Paz Muñoz welcomes informal email enquiries before submitting an application (m.munoz-herranz@lancaster.ac.uk). Please note that we cannot receive applications by email as they must be processed centrally.

Applications should be made via Lancaster University’s online application system.

Please indicate on your application that you are applying for this funded PhD project by declaring the title of the advertisement where prompted. You may use the project description as your research proposal to apply for this studentship.

Funding Details

The studentship will cover fees at the UK rate plus the standard maintenance stipend.

It may also fully or partially contribute to the fees and stipend of a self-funded international candidate, though it is advised that you enquire regarding this before applying.

Deadline:

Deadline 20^th January 2023. Shortlisted candidates will be interviewed in early February.