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If you want a career in pharmaceutical chemistry research, joining a PhD project at the Reading School of Pharmacy will put you on the right path.

This is a taster of some of the PhD projects you can be involved in at the University of Reading. To discuss the different projects available, please contact Dr Graeme Cottrell by emailing g.s.cottrell@reading.ac.uk.


CHEMICAL PROTEOMICS PROBES FOR CYSTEINE OXIDATION

With Dr Sarah Allman

The reversible oxidation of cysteine residues in proteins has been implicated in intracellular signalling events, activation of autophagy, protein folding and the maintenance of cellular redox balance. Oxidation reactions resulting in irreversible modifications are also associated with various disease states. As such, tools which allow us to identify proteins in the cell which are susceptible to oxidation have the potential to provide information about these processes.

This interdisciplinary project brings together elements of synthetic chemistry, analytical sciences and cell biology. It focusses on the design and synthesis of molecule probes to react with the initial product of this oxidation reaction, and examine the ability of these compounds to label proteins contain cysteine residues susceptible to oxidation.

DESIGN AND SYNTHESIS OF NOVEL CELLULAR IMAGING DYES

With Dr Sarah Allman

Within the cell, calcium ions act as a crucially important messenger, mediating a plethora of important signalling and signal transduction events. The ability to quantify and visualise the calcium status of the cell can therefore provide important insights into these pathways.

Small molecule dyes which respond to the calcium status of the cell are often used to probe such events. As with all tools designed to probe biological systems, however, it is important they exert minimal adverse effects on the cell or influence the process under study.

In this interdisciplinary project, you will use a combination of synthetic chemistry, analytical sciences and cell biology methods to design and test a series of novel indicator dyes designed to quantify cellular calcium signalling events whilst preserving normal cellular functions.

INTEGRATED WORKFLOWS FOR GLYCOMICS

With Dr Sarah Allman

Defects in protein post-translational modifications have been linked to a variety of disease states and developmental disorders. Glycosylation (the process by which carbohydrates are linked to the surface of biomolecules) is one of the most commonly observed protein modifications. Changes in both in the sugars displayed upon the surface of proteins and those released from cellular degradation pathways can provide insights into disease states, cellular metabolism and factors influencing protein catabolism.

In this project, you will develop skills in synthetic chemistry, chemical biology and analytical sciences and use them to develop tools to enable the isolation and structural characterisation of sugars from different sources. You will then examine how these workflows can be adapted to facilitate functional characterisation of biologically relevant protein-carbohydrate binding interactions.

STRUCTURE AND FUNCTION OF I-MOTIF FORMING SEQUENCES

With Dr John Brazier

The i-motif is a four stranded structure formed by cytosine rich sequences of DNA. These sequences are found in a high proportion of gene promoter sequences and maybe useful as a target to modulate gene expression. The sequence composition of the i-motif forming sequence is crucial to the stability of the structure and potential for therapeutic action. The project will focus on probing the sequence composition of i-motif forming sequences, and linking sequence to stability and function.

TARGETING TRIPLET REPEATING NUCLEIC ACID SEQUENCES WITH DNA BINDING AGENTS

With Dr John Brazier

Extended triplet repeat regions of DNA and RNA are associated with several diseases including Huntington's disease and myotonic dystrophy. In healthy human cells these repeat number in the 10s, but in a diseased state they number in the 100s-1000s. Targeting such long repeating sequences of DNA or RNA is very challenging, but could provide useful diagnostic information or therapeutic action. This project will investigate the use of bi-functional DNA binding molecules to cooperatively bind to repeating DNA sequence, and differentiate between different lengths of repeat.

THE SYNTHESIS AND ANALYSIS OF NOVEL ANTI-CANCER AGENTS: FLAVONOIDS

With Professor Helen Osborn

One of the major problems of cancer chemotherapy is that the drugs used have poor selectivities for cancer cells and cause damage to normal cells and organs. In recent years, flavonoids, a large class of natural products, have shown promising anticancer activities.

The aim of this project is to design and chemically synthesise a wide range of flavonoid derivatives and determine their anti-cancer activities and investigate key structural-activity parameters. Through this project you will gain expertise in advanced synthetic chemistry and analytical techniques as well as computational methods for drug design.


THE SYNTHESIS AND ANALYSIS OF NOVEL ANTI-CANCER AGENTS: PRODRUGS FOR MELANOMA 

With Professor Helen Osborn

One of the major problems of cancer chemotherapy is that the drugs used have poor selectivities for cancer cells and cause damage to normal cells and organs. For this reason, researchers have become interested in preparing non-toxic 'prodrugs' that are converted to the toxic drugs selectively at the tumour site, for example by enzymes that are only present at the tumour.

Within our group, we have expertise in developing prodrugs for melanoma and on this project you will have an opportunity to chemically synthesise targets that have been designed to be activated by the tyrosinase enzyme. These molecules will then be analysed using both chemical and enzymatic techniques to ascertain how the structural features of the prodrugs affect the release of the drug.


PHYTOCHEMICAL AND PRECLINICAL STUDIES ON MEDICINAL PLANTS

With Dr Katja Strohfeldt

Herbal and Complementary Medicines (HCM) is an area which is of growing importance to healthcare, so it is important to ensure that the products used fulfil the relevant quality standards. The aim of this project is to look at a range of selected plants, which are established or known for their traditional use in the treatment of infections, cancer or other relevant clinical issues to human health.

The research will include a full literature search, verification and extraction of plant material, full chemical analysis and the biological testing against a range of relevant bio-assays in order to understand their potential clinical application.

Within this project you will have the unique opportunity to work in a multidisciplinary team exploring new medicinal plants, studying their photochemistry and potential biological activity in order to establish quality standards for safe application.


SYNTHESIS AND EVALUATION OF NOVEL METAL-BASED ANTI-CANCER DRUGS

With Dr Katja Strohfeldt

Metal-based drugs form an important part of chemotherapy, with cisplatinum being involved in the treatment of over 50% of all solid tumours. The aim of this project is to synthesize a novel class of potential anti-cancer agents, which contain a range of body-own proteins.

This will allow us to circumvent two of the major drawbacks when using metal-based anti-cancer agents in a clinical setting: low aqueous solubility and low selectivity of the metal-based compound to the tumour tissue.

Within this project you will have the unique opportunity to work in a multidisciplinary team using new synthetic and analytical methodology, studying different drug delivery systems (formulation and analysis) and evaluating their cytotoxic profiles.

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