Research Interests
Functional molecules and materials that solve problems
My research interests stem from my desire to find chemical solutions to problems which plague mankind. These are centered around supramolecular, medicinal, polymer and materials chemistry, and include carbohydrate chemistry, flow chemistry and the application of chemical solutions to biological problems. Broadly speaking, it's the synthesis of functional new molecules, followed by their analysis and application to solve a specific problem.
Polymer Nanofibers For Nanomedicine Applications
My research in the Manners lab focuses on the applications of low dispersity nanomaterials produced via 'living' crystallization-driven self-assembly (CDSA). CDSA Is a powerful bottom-up method for producing nanomaterials with precisely controlled sizes, shapes, and surface functionality. CDSA is especially useful for generating non-sperical nanostructures, such as 1D nanofibers and 2D platelets. Since I joined the group, we have developed several different systems that are capable of entering cells, and carrying cargo of various sorts. We are uncovering fundamental new insights into how these unique 1D and 2D polymer materials interact with biological systems, which can help inform a new generation of polymeric nanomedicines. I am currently involved with all aspects of applying these materials into nanomedicine, ranging from technology to improve scalability, to new material design, new applications of existing materials, and the biological effects of materials currently developed. It's loads of fun, and every time we learn something new we just end up with even more questions to answer!
PhD Research In the Galan Group
PhD Supervisor: Professor M. Carmen Galan
Can Sugars Cure Cancer?
Cancer is one of the leading causes of death in the developed world. One of the problems that makes cancer so hard to treat is the fact that it’s caused by mutations of healthy cells within our bodies. Thus a great deal of scientific research is devoted to developing new selective ways to target tumour cells whilst leaving healthy cells alone. What exactly is cancer? Find out here.
Whilst many people picture DNA to exist in its double helix form, DNA can actually exist in a wide range of structures from single stranded DNA up to 4 stranded or quadruplex DNA. This type of DNA structure is a relatively new discovery, which occurs in numerous regions throughout the cells in your body and is especially prevalent in cancer cells. Quadruplex DNA forms the basis of several potential anti-cancer drug targets. Perhaps the most well-studied involves the enzyme telomerase, which is responsible for providing cancer cells with their immortality. Telomerase causes cellular immortality by binding to a region of DNA called telomeric DNA. The DNA in this region can however form these 4 stranded ‘G-quadruplex’ structures, and by doing so it inhibits the telomerase enzyme, and leads to errors in DNA replication and consequently cell death.
This is where chemists like myself come in. If you can encourage the formation of these G-quadruplex structures in your telomeres by binding a small molecule to them, it will inhibit telomerase. Telomerase is overexpressed in 90% of cancer cells, but not expressed in healthy cells, so telomerase inhibition leads to the selective death of cancer cells over other healthy cells. When other G-quadruplex anti-cancer targets are considered too, one small molecule that is capable of binding to G-quadruplex DNA can kill cancer cells in multiple ways, resulting in a potent anti-cancer effect. Despite the considerable research in this area, we are yet to see a G-quadruplex interactive small molecule pass clinical trials and be an approved medication. This is smething we hope to change.
My project (which was part funded by Novartis and the first in the group on this topic) was aimed at looking to see if sugars (carbohydrates) such as Glucose can be modified and used as small molecules which bind to G-quadruplex structures. Other qudruplex binding molecules are poorly water soluble and are excreted by the body quickly, which is one of the reasons why none of them have been successful to date. Carbohydrates can overcome some of these problems, and to date have recieved limited attention, so we were hoping to use them to develop some new quadruplex active anti-cancer drugs!
Over the course of my PhD, I designed, developed and synthesized a completely new class of carbohydrate-aromatic conjugates. The library of around 30 new compounds was tested for the ability to stabilise therapeutically relevant DNA structures in a variety of different experiments, as well as testing their potential anti-cancer activity in vitro. Several interesting leads were identified, which resulted in several publications and further research by others in the group, which today remains active in the G-quadruplex field!
Taking this project from it's inception as an idea through to in vitro testing was incredibly rewarding, and I developed skills and expertise across a wide range of drug development techniques in the process. These include chemical synthesis, purification of challenging compounds by normal-phase and reverse-phase flash and preparative chromatography, analytical HPLC, mass spectrometry, NMR, Isothermal Titration Calorimetry (ITC), Circular Dichroism (CD), UV-Vis & Fluorescence Spectroscopy, Molecular Modelling, Computer Aided Drug-Design, Cell culture, cytotoxicity assays, data processing and much more. It was a really interesting PhD project, in a great group, that I really enjoyed!
Other Research Experience & Previous Projects
Doctoral Candidate - Novartis Institute for Biomedical Research (NIBR), Basel, Switzerland – Dr. G. J. Hollingworth
“Carbohydrate-based selective quadruplex DNA binding ligands with anti-cancer activity”
As part of my PhD project, I was lucky enough to be able to undertake a paid 3 month industry placement at Novartis' headquarters in Basel, Switzerland. Here I continued working on my PhD project while gaining valuable experience of how 'big pharma' companies operate. While at Novartis, I started several collaborations with Novartis scientists who were experienced in areas of interest to me. One such collaboration was international with a scientist at NIBR in Cambridge, MA, USA who was part of the computer-aided drug design team. They helped me to develop a model for docking and virtually screening new compounds, something that I pursued further after my placement had ended.
JSPS Summer Programme Fellowship - J. I. Yoshida Research Group, Kyoto University, Japan
“Flow micro-reactor based cationic living polymerizations: Studies on initiation by electrogenerated acid and glycosyl cations”
In the summer of 2014, I visited Japan after winning a prestigious fellowship from the Japan Society for the Promotion of Science (JSPS) as part of their Summer Programme. I visited the lab of Professor Jun-ichi Yoshida, a world expert in flow micro-reactor chemistry who is based at Kyoto University. Prof. Yoshida conducts research on flow micro-reactor based polymerisations, especially cation-pool initiated living polymerisations and ultrafast reactions in flow micro-reactors or ‘flash chemistry’. My project was based on producing new biopolymers by initiating a living polymerization with glycosyl cations (carbohydrates) under flow micro-reactor conditions. This is quite an ambitious task, which combines two areas of Prof. Yoshida’s research. My project yielded interesting results, and I ended up working on solving a 30 year old problem regarding the source of electrogenerated acid in the process of trying to achieve my goal! I gained lots of experience and many new skills, including how to design, build and work with flow reactors as well as writing successful research proposals. Building relations with Prof. Yoshida was an invaluable experience and I would love the opportunity to return to Japan in the future!
More information about my trip to Japan can be found here.
J. C. Morales Research Group, CSIC Cartuja, Sevilla, Spain
“Carbohydrate-based selective quadruplex DNA binding ligands with anti-cancer activity”
As part of my PhD project, I was also able to undertake a 2 month placement in the lab of my co-supervisor, Dr. Juan Carlos Morales at the CSIC IIQ in Sevilla, Spain. being able to live and work in another country for several months was an amazing opportunity, and I thoroughly enjoyed every minute of it. Here I was involved with learning some of the techniques necessary for testing the new compounds that I had developed.
BCS-CDT Research Sabbatical 3 - A. P. Davis Research Group, University of Bristol, UK
“Synthetic Chloride Anion Carriers as Transmembrane Transporters”
In this research broadening sabbatical I was working with Professor Anthony Davis on developing cholapod based synthetic chloride anion carriers. These compounds have potential use as transmembrane transporters for use with chanelopathies such as cystic fibrosis. I synthesized two novel receptors, and studied their activity along with the activity of previously synthesized receptors to establish a structure-activity relationship. These receptors were analyzed for their activity in three different ways: firstly their affinity for chloride anions was quantified through NMR titration and also using an extraction based method which allows for the determination of the binding constant (Ka) and has a higher detection limit than NMR titration. Secondly the cholapod’s ability to permeate a cell membrane was tested through a transport assay which uses vesicles. The influx of chloride ions was measured by using a chloride sensitive fluorescent dye. The data obtained on one of the receptors developed by me was used as a control cholapod receptor in a pulbication by the group in Angewandte Chemie.
BCS-CDT Research Sabbatical 2 - V. K. Aggarwal Research Group, University of Bristol, UK
“Asymmetric Synthesis of Tertiary Alcohols & Amines by Lithiation-Borylation Methodology”
In this research broadening sabbatical I was working with Professor Varinder Aggarwal FRS on producing multigram scales of enantioenriched tertiary boronic esters, and then exploring their transformations into enantioenriched tertiary alcohols and α-tertiary amines. The highlights of this rotation was successfully producing over 5 grams of the tertiary boronic ester, in a 94 % yield and with a >99:1 e.r. This material was sold to sigma-aldrich, and I was the first CDT rotation student who managed to make 5 grams of this material with an e.r. of >99:1 (high enough quality to be used by Aldrich). The last part of my project was involved with developing the conversion of the tertiary pinacol boronic esters into α-tertiary amines using a reagent developed by Morken. Morken’s chemistry didn’t work for tertiary substrates, so achieving a 40 % yield in this reaction was a pleasing result.
BCS-CDT Research Sabbatical 1 - D. F. Wass Research Group, University of Bristol, UK
“Catalytic Upgrading of Ethanol for Advanced Biofuels”
In this research broadening sabbatical I was working with Professor Duncan Wass on developing and testing ruthenium based catalysts for the upgrading of ethanol to n-butanol, an advanced biofuel. A novel catalytic system for the coupling of ethanol to selectively produce butanol via Guerbet type chemistry was discovered by the group. My project was involved with exploring phosphine-amine based ligands, with a view to improve upon the yield of n-butanol produced whilst maintaining the selectivity. I developed and tested 3 new ligands, and improved upon the previous highest yield of n-butanol achieving a yield of 28 % making it the best ligand tested to date. I also tested and proved that the phosphine- amine ligands act at a similar rate if the ligands are used in situ as their quaternary amine salts. This was an important development as the main application of this chemistry is in industrial processes, where the use of conventional air sensitive phosphine ligands is complicated and expensive. The use of air and moisture stable quaternary amine ligands is therefore an important improvement. I also produced a reaction progress kinetic plot for one of the ligand systems, which is useful for insights into the mechanism and deactivation of the catalyst. My work during this sabbatical contributed to a publication by the group in ACS Catalysis.
Undergraduate Project - H. M. Colquhoun Research Group, University of Reading, UK
“Polymer-supported Molecular Tweezers as Sensors for Polynitroaromatic Compounds”
Under the supervision of Professor Howard Colquhoun, my dissertation was aimed at developing polymer-supported molecular tweezers for use as sensors to detect polynitroaromatic compounds (NACs) such as TNT. This was a very interesting project that involved a combination of synthesis as well as a wide range of analytical techniques. The molecular tweezers used were of a similar design to the tweezers used in my summer project, with the vital difference that there was no electron deficient moiety present. The idea behind this was that by attaching the molecular tweezer onto a polymer, electron deficient aromatic species such as TNT would intercalate with the tweezer, and induce fluorescence quenching of the electron rich units. The polymer chosen had to display good mechanical properties for this application. Overall, two different novel polymer based tweezer systems were developed, with a total of 7 steps of synthesis each. Analysis consisted of using a non-explosive model nitoaromatic (2-5 dinitrobenzonitrile) and performing NMR Titrations, UV/Visible Titrations, Fluorescence quenching titrations, and solid state sensing studies (performed by casting thin films of the polymer). These experiments proved that the polymers did indeed exhibit fluorescence quenching of NACs, as well as having improved mechanical properties. Furthermore these new polymers could be cast into films – which was an improvement on previous work.
UROP Summer Placement - W. C. Hayes Research Group, University of Reading, UK
“Synthesis of novel healable supramolecular polymers through self-complimentary π-π stacking interactions”
Working under Professor Wayne Hayes, I undertook research into the development of supramolecular self-healing polymers. These polymers consisted of an electron deficient core attached to an electron rich molecular tweezer to form a motif which self-assembled through complimentary π-π stacking interactions in a ‘roman handshake’ style. These motifs were then grafted onto a polymer to assess their ability to self-heal under stress. I was responsible for choosing the polymer scaffold, developing the synthetic route and synthesizing the resulting polymeric materials. After choosing to develop a novel methacrylate based copolymer, I successfully synthesized several new molecules on a multigram scale including 2 novel polymers and presented my work to the group.
Junior Analyst, CEM Analytical Services Ltd, Ascot, Berkshire, UK
While working as an analyst for CEMAS, I was responsible for preparing and analysing samples from agrochemical field trials. I worked with a wide variety of equipment including UPLC/MS/MS and LC/MS with Symbiosis as well as GC and Ion Chromatography. All work done was compliant with GLP guidelines.
orcid.org/0000-0002-7635-8733