Hulme Group research integrates synthetic methodology development with chemical biology to provide molecular level insight to challenges in biology and medicine.
Chemical Biology & Medicine
We focus on the synthesis and chemical biology/ medicinal chemistry applications of natural products, and combine this with the design and synthesis of small molecule probes to investigate the interactions of biomolecules both in vivo and in vitro. We use a range of techniques (affinity chromatography, FRET, NMR footprinting, MS, Raman spectroscopy etc.) to investigate how biomolecules such as glycosaminoglycans, steroids and peptide aptamers bind to their cellular targets. Past and current synthetic targets for the group include the pyrrolidine antibiotic anisomycin which activates the stress kinase pathways, a known cancer therapeutic target; the marine natural product bisebromoamide which has been shown to induce apoptosis through ERK and mTOR inhibition in renal cancer cells; and disorazole C1 which binds to tubulin at a site which is orthogonal to both taxol and vinca alkaloid anti-cancer drugs. We are also interested in the design and synthesis of stapled peptides, targeting the disruption of protein-protein interactions using this novel class of potential therapeutics. We collaborate with groups within the Edinburgh Cancer Research Centre [Ball, Brunton, Carragher, Frame, Patton], the Scottish Centre for Regenerative Medicine [Kunath, Williams] and internationally [Fearnhead (NUI Galway, Ireland)] to develop potential therapeutic leads.
The Hulme group has ongoing projects in (1) the development of tiny (a few atoms) labels for the in vivo Raman imaging/quantification of drugs/drug candidates in cells and mice – in collaboration with Val Brunton at the Edinburgh Cancer Research Centre; (2) mono-conjugation of biomolecules with fluorophores for super resolution imaging – in collaboration with Rory Duncan at Heriot Watt; (3) converting PET images of atherosclerotic plaques into higher resolution fluorescent images – in collaboration with Fabio Nudelman in Chemistry and Marc Dweck at QMRI; (4) pre-targeted imaging of inflammation using bespoke biotinidase-resistant biotin linkers – in collaboration with Patrick Hadoke at QMRI.
Hulme group natural product targets span a number of different classes of metabolite, but an overriding theme is that they interact with their biological targets through several, or many, chiral groups. Some of the natural product targets which have recently been successfully tackled by the group are: the mixed PKS/NRPS cytotoxic marine natural product disorazole C1; a thiazoline analogue of the cytotoxic NRPS-derived peptide bisebromoamide, and the cytotoxic marine polyketide octalactin A. Past targets have included the antifungal protein synthesis inhibitor anisomycin; iminosugar immunomodulators such as DAB-1, CYB-3, and nectrisine; tetrahydroisoquinoline antibiotics such as pancratistatin; and products of mixed PKS-NRPS biosynthetic pathways, such as the unusual aminopolyol zwittermicin A.
The Hulme group are interested in the light fastness of historic natural products dyestuffs (see Chem. Soc. Rev., 2005) and have investigated the light-ageing of natural yellow flavonoid dyes such as those found in the plants weld and dyers greenweed, and red/black neoflavonoid dyes such as those found in brazilwood. Sample sizes are necessarily very small and the Hulme group have pioneered the use of LC-MS and more recently UPLC in the analysis of dyestuffs, working on material from the NMS, Burrell, Bodleian, Historic Royal Palaces, and V&A collections over the past 15 years. From 2002-2005 the group took part in the largest project funded under the EC FP5 Cultural Heritage Programme (Contract: EV4K-CT-2001-00048) on the Monitoring of Damage in Historic Tapestries (MODHT). Royal tapestries were extremely prestigious and very expensive pieces (typically costing as much as a battleship each) and represent a rich part of European cultural heritage. From 2009-13 the group had a studentship from the EPSRC/AHRC funded Science and Heritage programme. Past research group members have gone on to work at the Swiss Institute of Art in Zurich, the National Gallery in London and National Museums Scotland.
The photostability of dyestuffs is a modern problem as much as an historic one. With the rapid rise in digital cameras and home-printing of photographs the kind of problems that can arise can easily be seen in faded old pictures.
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