Welcome to the Research homepage for Steven Street. This website explains more about who I am, what I do, what I've achieved so far, and what I hope to achieve in the future! I have just completed my PhD in synthetic organic chemistry and chemical biology as part of the Bristol Chemical Synthesis Centre for Doctoral Training (BCS-CDT) at the University of Bristol.
Chemistry underpins everything around us, from the interactions of components within the cells inside our body to nuclear fusion processes occuring in the cores of stars millions of lightyears away. Despite making up the entire universe, it remains one of the most under-rated sciences, with physicists dominating the public perception of scientists. This is despite the tremendous contribution that chemists and chemistry make to our society, tackling everything from climate change and disease to the technology behind your TV!
Chemistry is the lowest level of system which allows for design. Physics cannot be designed, only understood, whereas chemical systems have been manipulated and created by nature since the dawn of time. Now humans are also learning how to create and manipulate chemical systems, though our understanding and capabilities lack far behind nature's.
Being a synthetic organic chemist means that I like to play with 'molecular lego bricks' to create new molecules which have never existed before. These new chemical structures can potentially be used to solve some of the many problems which the world faces today, such as improving healthcare, treating disease, developing and storing clean energy, and tackling climate change. I started my PhD at the Bristol Chemical Synthesis Centre for Doctoral Training (BCS-CDT) back in 2012 to work on solving problems such as these, and consequently chose to work with Prof. M Carmen Galan developing new carbohydrate-based molecules that are capable of binding to G-Quadruplex DNA, an important area of anti-cancer drug design.
Using chemistry to make the world a better place...
My motivations for being a scientist stem largely from a desire to help make the world a better place. We live in a world constantly faced by threats, some which are natural, and others which are down to human activity. life is extremely fragile, and we are all part of an incredibly complex, intertwined, co-dependant system. Every action we take has an effect both on others, and the larger world as a whole. Whether it is through develping new drugs to treat diseases that claim countless numbers of lives, or developing new ways to combat climate change and generate clean energy, I wish to make my own small contribution to help solve some of the important challanges that we as humans collectively face.
Functional molecules 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 problem.
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 several regions throughout the body, and is especially prevalent in cancer cells. An enzyme called telomerase is responsible for providing cancer with its cellular immortality, and works 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 inhibit the telomerase enzyme.
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, this will then inhibit telomerase. Telomerase is overexpressed in 90% of cancer cells, but not expressed in healthy cells so inhibition of this enzyme leads to the selective death of cancer cells over other healthy cells.
My project (which is part funded by Novartis) is 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, which is one of the reasons why none of them have so far made it successfully to market to date. Carbohydrates can overcome these problems, and to date have recieved limited attention, so hopefully we can 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 were tested for their ability to stabilise therapeutically relevant DNA structures in a variety of different assays, as well as testing their ability to kill cancer cells in vitro. Several interesting leads have been identified, which include compounds with very interesting and unique selectivity profiles.
Taking this project from it's inception as an idea through to in vitro testing has been incredibly rewarding, and I have 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.
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’m currently considering returning to Japan to continue my research after my PhD under a JSPS Postdoctoral award.
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.
4. “Investigating UV-Induced Electron-Driven Proton Transfer in a Chemically Modified A•T DNA Base Pair” – Röttger, K.; Marroux, H. J. B; Chemin, A. F. M.; Elsdon, E.; Oliver, T. A. A.; Street, S. T. G.; Henderson, A. S.; Galan, M. C.; Orr-Ewing, A. J.; Roberts, G. M. J. Phys. Chem. Lett. 2017, 121, 4448.
3. "Divalent Naphthalene Diimide Ligands Display High Selectivity for the Human Telomeric G-quadruplex in K+ Buffer" – Street, S. T. G.; Chin, D.; Hollingworth, G. J.; Morales J. C.; Galan, M. C. Chem. Eur. J. 2017, 23, 6953.
Also see the Inside Front Cover here.
2. “Catalytic Conversion of Ethanol to n-Butanol using Ruthenium P-N ligand complexes” – Wingad, R. L.; Gates, P. J.; Street, S. T. G.; Wass, D. F. ACS Catalysis 2015, 5, 5822.
1. “A Flexible Solution to Anion Transport: Powerful Anionophores Based on a Cyclohexane Scaffold” - Cooper, J. A.; Street, S. T. G.; Davis, A. P. Angew. Chemie Int. Ed. 2014, 53, 5609.
I recently won the "Drug Discovery" section of the I'm a Scientist: Get me out of here competition, and as the winner, I recieved £500 to use on an outreach activity of my choice.
My plan for the money is to create a careers website for secondary school students, who are making decisions about what subjects to study. This might be KS3 subjects in year 9, GCSE subjects in year 10, A-level subjects in year 12, or undergraduate degree subjects in year 13.
The website will be based on real people, real careers and real research, and will be organised by school subject. Students will be able to log on and discover a wealth of potential career and research options covering all walks of life, all organised by the most relevant subject to the career, and based on real people, who made real decisions.
Filling out the questionnaire takes jut 5 minutes of time, and will influence the decisions that thousands of students make, help others to avoid common pitfalls / mistakes, and help others to appreciate school subjects that are perhaps commonly overlooked (or even not part of the curriculum!)
When I was at school, nobody ever spoke to me about what jobs different subjects can lead to. This was especially the case in science and engineering, where a lot of jobs are in research, yet nobody ever tells you what research is! I want to change this.
The first time I ever spoke to somebody who was actually a scientist was when I was looking around universities in year 12, which was in my opinion far too late! I want to change this too.
I think it would be useful for young people to be able to talk to real scientists, engineers, and people from other careers, and find out the what they work on, and what their jobs are like. This is especially important in subjects like chemistry, where what you learn at school is very different to what you can do in research, and in school it might not seem as exciting/useful or relevant to life as it actually is!
I think a lot of people who would make great scientists choose to not study science further at school because they don’t know where it can take them.
THIS I want to change. But I need your help!
Who we would especially like to hear from
I want to hear from everyone. This website will only be as good as the database that it is built on, and a breadth of subjects will only be present if people from a variety of walks of life take the time to fill out their details.
I would especially like to hear from anyone who has an interesting job, an interesting project or area of research, or anyone who has started their own company. I would like to hear from a variety people from 'commonly considered' careers such as medicine, law, accountancy, teaching, police, fire service, etc... as well as many careers that might be similar, but commonly overlooked, such as scientific research, patent law, etc!
So basically we want to hear from everyone... This is your chance to 'represent' your subject area and career to students, and be part of something exciting!
The survey is live, waiting to be filled out by a broad range of recipients, and the website is currently under construction. Watch this space for more details!
To fill out the questionnaire, see https://www.surveymonkey.co.uk/r/GKDQDV8