We are an organic chemistry research group working in a number of areas of organic chemistry and chemical biology, including:
- (1) the development of new synthetic methodology
- (2) the isolation and synthesis of novel small molecule antibiotics
- (3) the synthesis of functional fluorophores for biological imaging
- (4) the development of high throughput methods in X-ray crystallography
Encapsulated Nanodroplet Crystallisation of Organic Soluble Small Molecules (ENaCt)
Working with Drs Probert and Heaps (NCL), Prof Steed (Durham) and Dr Thaw (SPT Labtech), we have developed a general method for the high-throughput nanoscale crystallisation of organic-soluble small molecules, Encapsulated Nanodroplet Crystallisation (ENaCt). ENaCt provides crystals suitable for X-ray analysis, allowing structural and de novo absolute stereochemical assignment for a diverse and challenging range of small molecules (bioactives, natural products, organometallics etc.) as well as acting as a tool for new polymorph discovery.
Tyler ARM, Ragbirsingh R, McMonagle CJ, Waddell PG, Heaps SE, Steed JW, Thaw P, Hall MJ, Probert MR. Encapsulated Nanodroplet Crystallisation of Organic-Soluble Small Molecules. Chem. 2020, accepted.
Cell Sneak Peak (Preprint) https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3509916
ChemRxiv (Preprint) https://doi.org/10.26434/chemrxiv.11366054.v1
Natural Product Antibiotics from Actinomycetes
Actinomycetes are bacteria rich in bioactive natural products, many of which show antibiotic properties. Working in collaboration with a microbiology team we are interested in the isolation, structural solution and bioactivity investigation of new antibiotic natural products.
- Mosaei H, Molodtsov V, Kepplinger B, Harbottle J, Moon C, Jeeves R, Ceccaroni L, Shin Y, Morton-Laing S, Marrs ECL, Wills C, Clegg W, Yuzenkova J, Perry JD, Bacon J, Errington J, Allenby NEE, Hall MJ, Murakami KS, Zenkin N. Mode of Action of Kanglemycin A, an Ansamycin Natural Product that Is Active against Rifampicin Resistant Mycobacterium tuberculosis. Molecular Cell 2018, 72(2), 263-274.
- Kepplinger B, Morton S, Seistrup K, Marrs E, Hopkins A, Perry J, Strahl H, Hall M, Errington J, Allenby N. Mode of Action and Heterologous Expression of the Natural Product Antibiotic Vancoresmycin. ACS Chemical Biology 2018, 13(1), 207-214.
- Tyler A, Sejzi HM, Morton S, Waddell PG, Wills C, McFarlane W, Gray J, Goodfellow M, Errington J, Allenby N, Zenkin N, Hall MJ. Structural reassignment and absolute stereochemistry of madurastatin C1 (MBJ-0034) and the related “aziridine” siderophores: madurastatins A1, B1 and MBJ-0035. Journal of Natural Products 2017, 80(5), 1558–1562.
Chiral BODIPY Fluorophores
The synthesis and resolution of a class of chiral organic fluorophores, axially chiral 4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes (Ax*-BODIPY), is described. Ax*-BODIPYs were prepared through a modular synthesis combined with a late stage Heck functionalisation. Resolution was achieved by preparative chiral HPLC. Absolute stereochemical assignment was performed by comparison of experimental ECD spectra with TD-DFT calculations.
- Clarke R, Ho KL, Alsimaree AA, Waddell PG, Bogaerts J, Herrebout W, Knight J, Pal R, Penfold T, Hall MJ. Circularly Polarised Luminescence from Helically Chiral ‘Confused’ N,N,O,C-Boron-Chelated Dipyrromethenes (BODIPYs). ChemPhotoChem 2017, 1(11), 513-517.
- Alnoman RB, Rihn S, OConnor DC, Black FA, Costello B, Waddell PG, Clegg W, Peacock RD, Herrebout W, Knight JG, Hall MJ. Circularly Polarized Luminescence from Helically Chiral N,N,O,O-Boron Chelated Dipyrromethenes.Chemistry - A European Journal 2016, 22(1), 93-96.
- Lerrick RI, Winstanley TPL, Haggerty K, Wills C, Clegg W, Harrington RW, Bultinck P, Herrebout W, Benniston AC, Hall MJ. Axially Chiral BODIPYs. Chemical Communications 2014, 50(36), 4714-4716.
Grignard Reagents as Reducing Agents
2,2,2-Trichloro-1-arylethanones undergo high yielding reductions to the corresponding 2,2-dichloro-1-arylethanones in the presence of RMgX. A single electron transfer mechanism for the reaction is proposed based on trapping experiments. Reaction of the intermediate enolates with a range of electrophiles is described, providing a convenient route to substituted α,α-dichloro-β-hydroxyketones and related molecules.
- Essa AH, Lerrick RI, Çiftçi E, Harrington RW, Waddell PG, Clegg W, Hall MJ. Grignard-mediated reduction of 2,2,2-trichloro-1-arylethanones. Organic & Biomolecular Chemistry 2015, 13(20), 5793-5803.
- Essa AH, Lerrick RI, Tuna F, Harrington RW, Clegg W, Hall MJ. Reduction of 2,2,2-trichloro-1-arylethanones by RMgX: mechanistic investigation and the synthesis of substituted α,α-dichloroketones. Chemical Communications 2013, 49(27), 2756-2758.
Northern Accelerator Executive into Business
Northern Accelerator CCF (PoC): Robot Assisted Micro-crystallisation Platform for Polymorph Screening and Structural Solution – Prototype Workflow Development, Industrial Demonstrations and Market Development, £48,683
MICA: Novel mode of RNA polymerase inhibition by a new natural rifamycin, which is active against rifampicin-resistant RNA polymerase, Medical Research Council (MRC), £603,841
Industrial Demonstration of Newcastle High Throughput Crystallisation Screening Platform, Higher Education Innovation Fund (HEIF), £11,845
High throughput structural elucidation of plant natural products and agrochemical metabolites, N8 Research Partnership, £31,580
Metabolomics by Automated Crystallography (MbAC): Solving the Structural Elucidation Bottleneck in Natural Product Discovery and Bioengineering through Automated Crystallisation and Single Crystal X-Ray Diffraction, NPRONET, Biotechnology and Biological Sciences Research Council (BBSRC), £43,843
Bill toScale-up and Structural Elucidation of Novel Natural Product Antibiotics from the Demuris Actinomycete Collection, NPRONET, Biotechnology and Biological Sciences Research Council (BBSRC), £10,000
Studying the development of a new natural product antibiotic for the treatment of ESKAPE infections, Rosetrees Trust, £54,171
A New Antibiotic for Gram Positive Bacterial Infections, Medical Research Council (MRC), £29,282
A Novel Crosslinking Strategy for MS Structural Biology, Biotechnology and Biological Sciences Research Council (BBSRC), £116,056
Probing the Mechanisms of dSTORM Reporters, Biotechnology and Biological Sciences Research Council (BBSRC), £118,521
Towards commercial application of a novel method to prevent and remove bacterial biofilms, Natural Environment Research Council (NERC), £137,802
Diels-Alder/Ene Reactions for the Multi-Component Synthesis, Engineering and Physical Sciences Research Council (EPSRC), £96,013