Department of Chemistry,
University College London,
T: +44 (0)20 7679 4623
Organic Chemistry and Chemical Biology
Section Head: Prof Jim Anderson
The Organic Chemistry and Chemical Biology section comprises 16 academic staff engaged in a variety of research activities that are underpinned by organic synthesis. Research activities cover a broad range of topics from the development of new reaction methodologies and catalysts, target asymmetric synthesis of molecules with profound biological activity, through to peptide, protein and DNA chemistry, radiochemistry and molecule imaging, single molecule detection, mass spectrometry, bionanotechnology, biocatalysis, chemical genetics and directed evolution. In much of this work interactions with biology and medicine is vital and a number of exciting projects are developing new therapeutics for treatment of a variety of diseases including infection, cancer and cardiovascular disease. Activities in the areas of Chemical Biology and Medicinal Chemistry are coordinated through the Centre for Chemical Biology.
The section is supported by grants from EPSRC, BBSRC, MRC, Wellcome Trust and Industry.
Below is a brief overview of some of the recent discoveries and inventions that have taken place in UCL's Organic Chemistry and Chemical Biology department as well as the on going research.
Research in my laboratory covers a broad portfolio of projects that combine contemporary synthetic organic chemistry methodology with highly adventurous, blue sky research. The basic theme in all of these projects is inventing fundamentally different ways of creating new organic structures in a stereocontrolled and, if applicable, catalytic fashion. This encompasses the development of new reaction methodology which is showcased in the synthesis of biologically active natural and non natural products.
Erik Årstad - Radiochemistry and Molecular Imaging
Our research is focused on the development of radioactive tracers for in vivo imaging using Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT). Nuclear imaging is highly sensitive and enables studies of a wide range of physiological processes in humans. Radiopharmaceuticals are now widely used for diagnosis of cancer, to support drug development and to study brain function. Development of radiotracers involves a broad range of disciplines, including physics, radiochemistry, medicinal chemistry, biology, pharmacology and medicine.
Our research group is focused on developing new methods in organic synthesis and chemical biology, and harnessing them in the design of therapeutics, clinical tools and probes of biological systems. We are particularly interested in investigating new approaches to the chemical modification of proteins, the construction and application of homogeneous antibody conjugates, and the photochemical control of biomolecules.
Stephen Caddick - Synthesis and Chemical Biology
More information about the Caddick Research Group can be found at: http://www.ucl.ac.uk/caddick-group
The Caddick Research Group has a wide range of research interests cutting across synthetic organic chemistry, organometallic chemistry, medicinal chemistry, chemical biology and drug discovery. We have a multi-disciplinary laboratory of around 12 researchers with skills in molecular / cell biology, bioinformatics and synthetic chemistry, with considerable industry links. Our research interests can be divided into three broad areas of activity.
1. Discovery research and innovation in organic synthesis
We are strongly committed to carrying out blue sky research in organic synthesis in which we test new concepts in organic synthesis. This is because new chemical reaction processes are vital if we are to make new molecular entities. A recent example has been our discovery that air can be used as a reagent to make carbon-carbon and carbon-nitrogen bonds. We have many areas of interest in organometallic chemistry, amino-acid chemistry, catalysis and a variety of other synthetic programmes.
2. Development of small molecule tools for applications in biology
We are committed to developing new approaches for the development of tool compounds to help understand fundamental biology and to help initiate studies in medicinal chemistry. In particular our work on sulfonates and sulfonamides has been successfully applied to a number of exciting biological targets from HIV to DDAH inhibition. We have a wide range of expert collaborators and some examples of current projects include: methylarginine processing enzymes (with Dr Leiper, MRC); nuclear transport of HIV (with Dr Fassati, UCL); β-adrenergic receptor antagonists (with Drs Baker, Vinter and Tinker, UCL); epicardial stem cell differentiation (with Prof. Riley, ICH); coagulation & respiratory disease (Prof Chambers, UCL)
3. Synthetic protein chemistry and chemical mutagenesis
Over the last few years we have become very interested in the power of organic synthesis for selective modification of proteins. In a very productive collaboration with Dr James Baker (UCL Chemistry) we have developed a number of new strategies for reversible and irreversible modification of proteins. Most recently we have applied this work to the development of a new GFP / FRET construct – which has been applied to cellular systems. Biological molecules are enormously important in the development of the next generation of diagnostics and therapeutics and our ability to carry out selective modification provides unique opportunities for applications in medicine and health.
4. ThioLogics – Delivering Homogeneous Protein Modification
Thiologics is a UCLB-owned company spun-out of the Department of Chemistry, UCL, in June 2011. The company aims to commercialise new bioconjugation technologies developed through collaboration between our group and Dr James Baker. ThioLogics is particularly focused on delivering technology that will enable the construction of homogeneous antibody drug conjugate therapeutics (ADCs) (www.thiologics.com).
Research activity in our group is focused on the use of synthetic organic chemistry to probe and solve biological problems. Many projects involve the development of new synthetic strategies to construct molecules as tools to identify or perturb biological targets, which can lead to the identification of novel compounds with improved biological properties. Current projects also include the use of biocatalytic synthetic strategies, and organic reactions in water including biomimetic chemistries. In particular, we are using transketolases, transaminases, and norcoclaurine synthases in single step biotransformations or synthetic biology pathways. We are also designing and synthesising new lipids for use in nanoparticle delivery applications, and as imaging reagents.
Stefan Howorka - Biomolecule engineering and single-molecule detection
The Howorka group works within nucleic acids chemistry and develops novel chemistries and functionally enhances nucleosides, nucleotides and oligonucleotides in order to open up new applications in Chemical Biology, Single-Molecule Sensing, and the Life Sciences. Research is pursued in three areas: (i) The synthesis of nucleoside and nucleotides analogues with light-sensitive and light-controlled moieties to create new biomedically important compounds for cell biological research. (ii) The preparation of oligonucleotides with hydrophobic tags to anchor the conjugates into lipid bilayers. This has lead to the construction of new membrane-spanning DNA nanopores for next-generation single-molecule sensing. The porous structures can also be exploited for cell biological research. (iii) The creation of linker chemistries to anchor nucleic acids to inorganic surfaces for ultrasensitive biosensing approaches. In previous research, I have been working on the use of chemical research tools to investigate the structure of a prominent bacterial membrane protein.
The Macmillan group is engaged in the semi-synthesis of modified proteins. Protein synthesis and semi synthesis will be important in unravelling the mechanisms of action of processes involving post-translationally modified (glycosylated, phosphorylated) proteins. This endeavour involves synthetic organic chemistry, molecular biology, protein expression and protein engineering. Other projects include glycosyltransferase engineering, antimicrobial peptide synthesis, and synthesis and utility of transition metal complexes.
Research in the Marson group involves both the uncovering of new synthetic organic methodology and the synthesis of novel organic compounds, either for use in chemical biology or medicinal chemistry. In the latter category are potent inhibitors of histone deacetylase (HDAC), as depicted in gold and magenta, docked into HDAC1 enzyme, and possessing in vitro IC50values down to 1 nM.
Research within the Motherwell group addresses a wide variety of fundamental questions from the invention of new and unusual reactions in organometallic and free radical chemistry through to molecular recognition, non covalent interactions and artificial enzymes.
Michael Porter - Synthesis of Complex Natural Products
Our research targets the synthesis of complex biologically active molecules which can then be used as probes to target biological function. Current targets have potency as RNA polymerase inhibitors, antibiotics and cytotoxins. We generally need to develop new methodology to carry out our syntheses, and this has led us into a variety of areas including metal carbenes, carbohydrate chemistry and photochemistry.
Our research is focused on the development of new methods for organic synthesis. In all cases, the research projects seek to provide novel solutions to challenging chemical problems, which will facilitate the synthesis of small, highly functionalised organic molecules with potential applications in drug discovery or chemical biology. Particular areas of interest include transition-metal catalysis, organoboron chemistry, multicomponent reactions, sustainable chemistry, and the synthesis of novel ring systems for medicinal chemistry.
Alethea Tabor - Chemical biology of membrane-active and cell-targeting peptide
We are developing new synthetic chemistry methodologies to synthesise biologically active peptides of unusual structure, and using biophysical techniques to probe their mode of action. We are currently working on the synthesis and lipid binding of the lantibiotic nisin; the design and synthesis of new targeting peptide and glycopeptides for use in ternary gene delivery vectors and in investigation antigen processing; and in new biomaterials for stem cell culture.
Our research is directed towards the synthesis of small molecule entities with biological activity. In particular we are interested in the preparation of peptidomimetics containing unnatural peptide bonds such as sulfonamides since this group has recently been shown to be a transition state mimetic of peptide hydrolysis and potent irreversible inhibitors of cysteine proteases. The course of this research has led us to a number of other areas including total synthesis of natural products and novel synthetic methodology.