Molecular Synthesis and Biological Chemistry

Research in this unit is focused on answering fundamental questions relating to molecular structure, chemical reactivity and physical properties. Our programmes concerning the discovery and development of efficient enabling methods and the design of bespoke functional molecules provide novel chemical entities and processes to tackle major societal challenges, spanning sustainability (energy, chemical feedstock, agriculture), next generation therapeutics and diagnostics. Our research is supported by the Centre for Chemical and Materials Analysis, which offers high quality spectroscopic analysis, including NMR, Mass Spectrometry, X-ray Diffraction and HPLC.

Areas of expertise

Asymmetric synthesis; carbohydrate chemistry; cascade reactions; catalysis discovery; catalysis design; functional molecules; lipids; scaffold design and molecular diversity; natural products; organic reaction mechanisms; organocatalysis; organometallic chemistry; reactive intermediates; reaction design; sustainable chemistry; synthetic organic chemistry; transition metal-mediated reactions; de novo peptide design; supramolecular chemistry; bioinorganic chemistry; synthetic DNA; foldamers.

 

Research unit leader

Areas of interest

Bioinorganic chemistry – de novo peptide design – lanthanides – coiled coils – artificial metalloproteins  – artificial metalloenzymes

Representative publication: Tuning coordination chemistry through the second sphere in designed metallocoiled coils.

L. N. Slope,  M. G. Hill,  C. F. Smith,  P. Teare,  F. J. de Cogan, M. M. Britton, A. F. A. Peacock, Chem. Comm., 2020, 56, 3729–3732.

anna-peacock-chem-comm-2020

Coiled coil, miniature designed protein scaffolds, can be exploited as novel ligands in inorganic chemistry, including for Lanthanide bindings. It is possible to tune the coordination chemistry, including the hydration state of the bound lanthanide, by careful selection of both first and second coordination sphere ligands, as well as binding site location. Gadolinium coiled coil complexes show promising relaxivity and are being explored in terms of MRI contrast agents.

Research unit members

Areas of interest

Supramolecular Chemistry · Host–Guest Chemistry · Mechanically Interlocked Molecules & Machines · Photophysics · Organic Electronic Materials

Representative publication: The Green Box: An Electronically Versatile Perylene Diimide Macrocyclic Host for Fullerenes

T. A. Barendt, W. K. Myers, S. P. Cornes, M. A. Lebedeva, K. Porfyrakis, I. Marques, V. Félix, P. D. Beer J. Am. Chem. Soc., 2020, 142, 349–364.

An Electronically Versatile Host for Fullerenes

Fabricated from more sustainable and functional materials, the efficiency of electron transfer and charge transport processes are also crucial to the development of devices such as organic light emitting diodes (OLEDs) and organic photovoltaics (solar cells). This work describes a rare example of electron transfer (eT) to C60 fullerene that is aided by its supramolecular encapsulation as a guest molecule inside the cavity of a macrocyclic host (above, right). The macrocycle also enhances electron transfer because, due to its green colour and akin to chlorophyll in a leaf (above, left), it effectively harvests light from a region where a significant fraction of the solar spectrum occurs. Hence the macrocycle is nicknamed the Green Box and provides promise as a new material for “greener” organic solar cells.

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Areas of interest

Supramolecular Chemistry and Self-assembly - Metal-organic Frameworks (MOFs) and Hydrogen-bonded Organic Frameworks (HOFs) - Crystal Engineering - Mechanically-interlocked Molecules: Rotaxanes and Catenanes - Surface self-assembly

Representative publication: Synthesis and Characterisation of Rylene Diimide Dimers Using Molecular Handcuffs

 L. Yang, P. Langer, E. S. Davies, M. Baldoni, K. Wickham, N. A. Besley, E. Besley, N. R. Champness, Chem. Sci., 2019, 10, 3723–3732.

neil-champness-chem-sci-2019Mechanically interlocked handcuffs provide a strategy to study rylene diimide dimers and to investigate their electronic and magnetic properties.

Areas of interest

Chemical Biology and Bioconjugation Strategies · Diversity-Oriented Synthesis · Medicinal Chemistry · Molecular Synthesis and Catalysis

Representative publication: Photoactivable Glycolipid Antigens Generate Stable Conjugates with CD1d for Invariant Natural Killer T Cell Activation

N. Veerapen, S. S. Kharkwal, P. Jervis, V. Bhowruth, A. K. Besra, S. J. North, S. M. Haslam, A. Dell, J. Hobrath, P. J. Quaid, P. J. Moynihan, L. R. Cox, H. Kharkwal, M. Zauderer, G. S. Besra, S. A. Porcelli, Bioconjugate Chem., 2018, 29, 3161–3173.

Photoactivable Glycolipid Antigens with CD1d

S. S. Kharkwal et al. Cancer Research, 2021, DOI: 10.1158/0008-5472.CAN-20-2219
Serial Stimulation of Invariant Natural Killer T Cells with Covalently Stabilized Bispecific T Cell Engagers Generates Anti-Tumor Immunity While Avoiding Anergy

A wide range of glycolipids bind to the protein CD1d.  Through judicious choice of glycolipid, the resulting complex is capable of activating iNKT cells to elicit an immune response.  Whilst careful optimisation of the glycolipid structure has delivered some potent iNKT-cell activators, dissociation of the glycolipid ligand from the CD1d molecule remains a problem for their potential therapeutic application in immunotherapies.  In this paper, we describe the first functional CD1d–glycolipid conjugate in which ligand dissociation is now no longer an issue.  This bioconjugation technology provides novel tool compounds for studying the mechanism of iNKT-cell biology and opens up a new immunotherapy strategy for future clinical application.

Areas of interest

Catalysis, organic methodology and synthesis, molecular design, organometallics, reaction mechanisms

Representative publication: Divergent C-H Insertion-Cyclization Cascades of N-Allyl Ynamides

H. V. Adcock, E. Chatzopoulou, P. W. Davies, Angew. Chem. Int. Ed., 2015, 54, 15525–15529.

Divergent C-H Insertion-Cyclization Cascades of N-Allyl YnamidesThis paper introduces  new reactivity in which competing and divergent pathways are controlled by choice of catalyst. New reactivity modes and sequences, including the unprecedented formation of gold carbenes by alkyne insertion into a CH bond, allow the selective and efficient preparation of different products from the same starting materials.

Areas of interest

Multi-component, atom economic organic synthesis, Chiral induction in molecular processes, Cation π-stacking, Carbohydrate and glycoconjugate recognition, Carbohydrate analytical chemistry

Representative publication: Derivatisation of parthenolide to address chemoresistant chronic lymphocytic leukaemia

X. Li, D. T. Payne, B. Ampolu, N. Bland, J. T. Brown, M. J. Dutton, C. A. Fitton, A. Gulliver, L. Hale, D. Hamza, G. Jones, R. Lane, A. G. Leach, L. Male, E. G. Merisor, M. J. Morton, A. S. Quy, R. Roberts, R. Scarll, T. Schulz-Utermoehl, T. Stankovic, B. Stevenson, J. S. Fossey* and A. Agathanggelou*
MedChemComm, 201910, 1379–1390.

A compound with anti-cancer properties from a feverfew plant

Areas of interest

Synthetic organic chemistry; Free radicals; Photochemistry; Natural product synthesis; Organosulfur and organoselenium chemistry; Peri-interactions; Medicinal chemistry

Representative publication: Carbamoyl radical-mediated synthesis and semipinacol rearrangement of β-lactam diols

M. Betou, L. Male, J. W. Steed, R. S. Grainger, Chem. Eur. J., 2014, 20, 65056517.

Carbamoyl radical-mediated synthesis and semipinacol rearrangement of β-lactam diolsThis paper reports a conceptually novel entry into bridged bicyclic lactams through ring expansion of fused beta-lactam diols. The core structures that can be prepared through this methodology are represented in a range of biologically important natural and non-natural products, and are ripe for further functionalization as rigid three-dimensional scaffolds for medicinal chemistry applications. The work builds on our group’s free-radical cyclisation methodology to access functionalized, cis-fused bicyclic lactams. The use of cyclic phosphoranes to rearrange diols has little precedent and through this work is shown to be potentially a more general alternative to the rearrangement of epoxides.

Areas of interest

Bioinorganic Chemistry; DNA and RNA Recognition; Metal-based Drugs; Nanoscience; Supramolecular Chemistry; Anti-cancer drugs; Anti-viral drugs; Imaging Chemistry for Biology and Medicine; Chemistry for Health; Biological Chemistry and Chemical Biology; Mechanically Interlocked Molecules

Representative publication: Rotaxanating Metallo-supramolecular Nano-cylinder Helicates to Switch DNA Junction Binding

C. A. J. Hooper, L. Cardo, J. S. Craig, L. Melidis, A. Garai, R. T. Egan, V. Sadovnikova, F. Burkert, L. Male, N. J. Hodges, D. F. Browning, R. Rosas, F. Liu, F. V. Rocha, M. A. Lima, S. Liu, D. Bardelang, M. J. Hannon, J. Am. Chem. Soc., 2020, 142, 20651–20660.

michael-hannon-j-am-chem-soc-2020A new class of rotaxane is created by wrapping a large cucurbit[10]uril macrocycle about a three-dimensional, cylindrical, nanosized, self-assembled supramolecular helicate as the axle. The resulting pseudo-rotaxane is readily converted into a proper interlocked rotaxane by adding branch points to the helicate strands that form the surface of the cylinder (like branches and roots on a tree trunk). The supramolecular cylinder that forms the axle is itself a member of a unique and remarkable class of helicate metallo-drugs that bind Y-shaped DNA junction structures and induce cell death. While pseudo-rotaxanation does not modify the DNA-binding properties, proper, mechanically-interlocked rotaxanation transforms the DNA-binding and biological activity of the cylinder. The number of branch points affords kinetic control over the drug de-threading and release.

Areas of interest

Main-group chemistry – Sustainable synthesis – Small-molecule activation – Catalysis – Photochemistry – Phosphorus

Representative publication: Photoinduced and Thermal Single-Electron Transfer to Generate Radicals from Frustrated Lewis Pairs

F. Holtrop, A. R. Jupp, N. P. van Leest, M. P. Dominguez, R. M. Williams, A. M. Brouwer, B. de Bruin, A. W. Ehlers, J. C. Slootweg,  Chem. Eur. J., 2020, 26, 9005–9011.

andrew-jupp-chem-cur-j-2020Frustrated Lewis Pairs (FLPs) are combinations of Lewis acids and bases that are sterically or electronically prevented from forming stable Lewis adducts. The unquenched acid and base sites, typified by bulky boranes and phosphines, respectively, can subsequently be exploited for small-molecule activation. We showed that light can be used to promote single-electron transfer from the Lewis base to the Lewis acid, forming a radical ion pair. This was characterised using UV-Vis spectroscopy (Figure a, above), EPR spectroscopy (Figure b) and transient absorption spectroscopy (Figure c). We were able to use the findings from this spectroscopic study to further interrogate the mechanism of the activation of dihydrogen (H2) and tin hydrides (R3SnH) by a range of FLPs

Areas of interest

Supramolecular chemistry, molecular recognition toolbox, metallosupramolecular architectures, host-guest chemistry, sensing

Representative publication: H-Bond Parameters for Cations

S. J. Pike, E. Lavagnini, L. M. Varley, J. L. Cook, C. A. Hunter, Chem. Sci., 2019, 10, 5943–5951.

sarah-pike-chem-sci-2019In this work, we have determined self-consistent H-bond donor parameters (α) for a series of organic and inorganic cations; including guanidinium, primary, tertiary and quaternary ammonium, lithium, sodium and potassium. The transferability of α parameters for cations between different solvents and different H-bond acceptor partners, allows for the reliable prediction of cation recognition properties in a range of different environments. These new H-donor parameters for cations will be useful in the development of our understanding and prediction of the behaviour of charged species in organic solution with applications in the design of new supramolecular systems.

Areas of interest

Luminescent probes, metal complex design, lanthanide chemistry and photophysics, nanoparticles for detection and monitoring, nanoprobes for drug delivery, disease targeting, photophysics, sensors

Representative publication: Iridium Nanoparticles for Multichannel Luminescence Lifetime Imaging, Mapping Localization in Live Cancer Cells

S. M. King, S. Claire, R. I. Teixeira, A. N. Dosumu, A. J. Carrod, H. Dehghani, M. J. Hannon, A. D. Ward, R. Bicknell, S. W. Botchway, N. J. Hodges, and Z. Pikramenou  J. Am. Chem. Soc., 2018, 140, 10242–10249. Iridium nanoparticles for imaging in cancer cells based on luminescence lifetime

We have developed gold nanoparticles detected by for two photon lifetime imaging using a short-lived (picosecond) and a long-lived (microsecond) lifetime signal, introducing two-channel imaging of nanoparticles leading to dual monitoring and imaging of the two signals independently. The studies not only show dual monitoring and imaging of two lifetime signals but also reveal unprecedented long lifetimes of the iridium nanoparticles in cells.

Areas of interest

Supramolecular chemistry, DNA sensing, modified nucleic acids, bioorganometallic chemistry, drug discovery, electrochemistry, fluorescence spectroscopy

Representative publication: Macrocyclic Metal Complex−DNA Conjugates for Electrochemical Sensing of Single Nucleobase Changes in DNA

J. H. A. Duprey, J. Carr-Smith, S. L. Horswell, J. Kowalski and J. H. R. Tucker  J. Am. Chem. Soc., 2016, 138, 746−749.

Macrocyclic Metal Complex & minusThe direct incorporation of macrocyclic cyclidene complexes into DNA via automated synthesis results in a new family of metal-functionalized DNA derivatives that readily demonstrate their utility through the ability of one redox-active copper(II)-containing strand to distinguish electrochemically between all four canonical DNA nucleobases at a single site within a target sequence of DNA.

Research Collaborations

MSBC team leaders are actively engaged with both industrial and academic partners within the UK and overseas as well as in collaborative projects across the University (School of Biosciences, School of Chemical Engineering and the College of Medical and Dental Sciences). This includes cross-disciplinary areas of research activity covered by the School of Chemistry's research themes, in particular Chemical Biology and Drug Discovery  and Chemistry for Healthcare Technologies.

Wider engagement

Molecular synthesis and Biological Chemistry play crucial roles in maintaining and improving our standard of life. Members of the Unit work closely with the Royal Society of Chemistry, the Society of Chemical Industry and the Royal Society as committee members, panel officers and Industry Fellows, to enable effective knowledge transfer across academia and industry and to enhance public awareness of this central area of Chemistry.

Contact

Enquiries about specific aspects of their research areas should be addressed to individual research group leaders. For more general enquiries about working with the MSBC Unit, please contact Dr Anna Peacock (MSBC Unit Lead). Information on various postgraduate (PhD and Masters) degree opportunities can be found on our postgraduate opportunities page.