Staff profile

Research Overview

My research group employs the mechanistic tools of physical organic chemistry to approach biological and synthetic chemistry problems. Key themes are the use of kinetics and the understanding and exploitation of physicochemical properties to enable more effective synthetic chemistry and bioconjugation procedures.

We use these ideas to deliver new methods for the preparation of nucleosides and nucleotides. Our ability to understand reactivity, especially in aqueous solutions, has enabled us to develop convenient bioconjugation procedures for nucleic acids. Our mechanistic approach is also applied to enzymes and understanding polysaccharide biopolymer systems.

Nucleosides and Nucleotides

We use aqueous and non-aqueous approaches to prepare nucleosides, nucleotides and phosphate ester mimics. Nucleosides are challenging substrates for synthetic chemists because of their solubility characteristics. They are often barely soluble in both organic solvents and water as a result of intermolecular interactions between nucleoside molecules. This problem is particularly acute for guanosine systems that form gels through hydrogen bonding interactions between guanine base units. We have overcome this problem through using basic conditions that remove a key hydrogen bond donor owing to its relatively low pK_a value (~9.5). Once the proton has been removed, substrates are soluble in aqueous media, however, this mandates the use of other tactics to allow functional group transformations to take place and subsequent purification of crude materials to be undertaken.

When organic solvents are employed, there is a requirement to use organic-solvent-soluble phosphate anions to prepare nucleoside di- and triphosphate species. Traditionally, alkylammonium salts have been used in this role, however, they are extremely hygroscopic and the water that they introduce can often have hugely deleterious effects on methods that are used to form phosphoanhydride bonds. We have prepared an alternative organic cation-pyrophosphate salt that does not take up moisture and is a convenient replacement for alkylammoniums.

Understanding Reactivity through Kinetics

We use kinetics to understand how molecules react with each other and how we can improve selectivity through understaning the relative rates of competing hydrolysis processes. Phosphorus (V) chlorides are often considered to be incompatioble with water, however, through understaning the relative rates of hydrolysis vs aminolysis processes we have developed 'click' processes that use POCl₃, PSCl₃ and their hydrolysis products, which are also effective phosphorylating agents.

We have found that phosphodichloridate anion and its thio analogue, which are both water soluble, are highly selective N-phosphoryaltion agents. Their selectivity derives from the fact that they are anionic AND electrophilic, thus they discriminate against hydroxide anion as a competing nucleophile, but not against neutral amines. Their half-lives are in the order of minutes making them convenient to use without needing rapid mixing systems.

Bioconjugates

We have developed suites of bioconjugation protocols for nucleic acid and polysaccharide biopolymer systems. Our nucleic acid studies build on our synthetic protocols that give ready access to guanosine derivatives that are initiators for T7 RNA polymerase. The 'handles' that are incorporated can be readily modified with affinity tags or fluorphores for immobilisation and detection purposes.

Polysaccharide biopolymers are the most abundant resources offered by nature and we can capitalise upon them through the development of new conjugation techniques that provide modified systems with new materials properties and bioactivities.

• Enzymes
• Nucleotides
• Physical Organic Chemistry
• Aqueous Reactivity
• Nucleic Acids
• Bioconjugation

• Bioactive Chemistry and Synthesis
• Physical Organic and Assembly

Chapter in book

• Hodgson, David R.W. (2017). Physicochemical Aspects of Aqueous and Nonaqueous Approaches to the Preparation of Nucleosides, Nucleotides and Phosphate Ester Mimics. In Advances in Physical Organic Chemistry. Williams, N.H. & Williams, I.H. Elsevier. 50.

Journal Article

• Murray, Jacob, Hodgson, David R. W. & O’Donoghue, AnnMarie C. (2023). Going Full Circle with Organocatalysis and Biocatalysis: The Latent Potential of Cofactor Mimics in Asymmetric Synthesis. The Journal of Organic Chemistry
• Guillen-Garcia, A., Gibson, S., Jordan, C., Ramaswamy, V., Linthwaite, V., Bromley, E.H.C., Brown, A.P. Hodgson, D., Blower, T., Verlet, J., Degiacomi, M., Palsson, L-O. & Cann, M.J. (2022). Allophycocyanin A is a carbon dioxide receptor in the cyanobacterial phycobilisome. Nature Communications 13: 5289.
• Linthwaite, V.L., Pawloski, W., Pegg, H.B., Townsend, P.D., Thomas, M.J., Brown, A.P., Hodgson, D.R.W., Lorimer, G.H., Fushman, D. & Cann, M.J. (2021). Ubiquitin is a carbon dioxide-binding protein. Science Advances 7(39): eabi5507.
• Quinn, Peter, Smith, Matthew S., Zhu, Jiayun, Hodgson, David R. W. & O’Donoghue, AnnMarie C. (2021). Triazolium Salt Organocatalysis: Mechanistic Evaluation of Unusual Ortho-Substituent Effects on Deprotonation. Catalysts 11(9): 1055.
• Rozatian, Neshat & Hodgson, David R. W. (2021). Reactivities of electrophilic N–F fluorinating reagents. Chemical Communications 57(6): 683-712.
• Rozatian, Neshat, Harsanyi, Antal, Murray, Ben J., Hampton, Alexander S., Chin, Emily J., Cook, Alexander S., Hodgson, David R. W. & Sandford, Graham (2020). Kinetics of electrophilic fluorination of steroids and epimerisation of fluorosteroids. Chemistry - A European Journal 26(52): 12027-12035.
• Bose, Sritama & Hodgson, David R. W. (2019). Stereoselective Syntheses of 3’-Hydroxyamino- and 3’-Methoxyamino-2’,3’-Dideoxynucleosides. Organic Letters 21(22): 9084-9088.
• Rozatian, Neshat, Beeby, Andrew, Ashworth, Ian W., Sandford, Graham & Hodgson, David R. W. (2019). Enolization rates control mono- versus di-fluorination of 1,3-dicarbonyl derivatives. Chemical Science 10(44): 10318-10330.
• Rozatian, Neshat, Ashworth, Ian W., Sandford, Graham & Hodgson, David R. W. (2018). A Quantitative Reactivity Scale for Electrophilic Fluorinating Reagents. Chemical Science 9(46): 8692-8702.
• Linthwaite, V.L., Janus, J.M., Brown, A.P., Wong-Pascua, D., O’Donoghue, A.C., Porter, A., Treumann, A., Hodgson, D.R.W. & Cann, M.J. (2018). The identification of carbon dioxide mediated protein post-translational modifications. Nature Communications 9: 3092.
• Eguaogie, Olga, Conlon, Patrick F., Ravalico, Francesco, Sweet, Jamie S. T., Elder, Thomas B., Conway, Louis P., Lennon, Marc E., Hodgson, David R. W. & Vyle, Joseph S. (2017). Nucleophilic displacement reactions of 5′-derivatised nucleosides in a vibration ball mill. Beilstein Journal of Organic Chemistry 13: 87-92.
• Conway, L. P., Mikkola, S., O’Donoghue, A. C. & Hodgson, D. R. W. (2016). The Synthesis, Conformation and Hydrolytic Stability of an N,S-bridging Thiophosphoramidate Analogue of Thymidylyl-3ʹ,5ʹ-Thymidine. Organic & Biomolecular Chemistry 14(30): 7361-7367.
• Eguaogie, Olga, Cooke, Leonie A., Martin, Patricia M. L., Ravalico, Francesco, Conway, Louis P., Hodgson, David R. W., Law, Christopher J. & Vyle, Joseph S. (2016). Synthesis of novel pyrophosphorothiolate-linked dinucleoside cap analogues in a ball mill. Organic and Biomolecular Chemistry 14(4): 1201-1205.
• Dano, Meisa, Elmeranta, Marjukka, Hodgson, David R.W., Jaakkola, Juho, Korhonen, Heidi & Mikkola, Satu (2015). Metal–ion promoted cleavage of nucleoside diphosphosugars: A model for reactions of phosphodiester bonds in carbohydrates. Journal of Biological Inorganic Chemistry 20(8): 1299-1306.
• Joubert, Fanny, Yeo, R. Paul, Sharples, Gary J., Musa, Osama M., Hodgson, David R. W. & Cameron, Neil R. (2015). Preparation of an antibacterial poly(ionic liquid) graft copolymer of hydroxyethyl cellulose. Biomacromolecules 16(12): 3970-3979.
• Townsend, P.D., Rodgers, T.L., Glover, L.C., Korhonen, H.J., Richards, S.A., Colwell, L.J., Pohl, E., Wilson, M.R., Hodgson, D.R.W., McLeish, T.C.B. & Cann, M.J. (2015). The role of protein-ligand contacts in allosteric regulation of the Escherichia coli Catabolite Activator Protein. Journal of Biological Chemistry 290(36): 22225-22235.
• Korhonen, H. J., Bolt, H. L. & Hodgson, D. R. W. (2015). A procedure for the preparation and isolation of nucleoside-5’-diphosphates. Beilstein Journal of Organic Chemistry 11: 469-472.
• Carvalho, A., O’Donoghue, A. C., Hodgson, D. R. W. & Kamerlin, S. C. L. (2015). Understanding Thio-Effects in Simple Phosphoryl Systems: Role of Solvent Effects and Nucleophile Charge. Organic and Biomolecular Chemistry 13(19): 5391-5398.
• Joubert, Fanny, Sharples, Gary J., Musa, Osama M., Hodgson, David R. W. & Cameron, Neil R. (2015). Preparation, properties, and antibacterial behavior of a novel cellulose derivative containing lactam groups. Journal of Polymer Science Part A: Polymer Chemistry 53(1): 68-78.
• Joubert, Fanny, Musa, Osama, Hodgson, David R. W. & Cameron, Neil R. (2015). Graft copolymers of hydroxyethyl cellulose by a ‘grafting to’ method: 15N labelling as a powerful characterisation tool in ‘click’ polymer chemistry. Polymer Chemistry 6(9): 1567-1575.
• Korhonen, Heidi J., Bolt, Hannah L., Vicente-Gines, Leyre, Perks, Daniel C. & Hodgson, David R. W. (2015). PPN pyrophosphate: A New Reagent for the Preparation of Nucleoside Triphosphates. Phosphorus, Sulfur, and Silicon and the Related Elements 190(5-6): 758-762.
• Conway, L. P., Delley, R. J., Neville, J., Freeman, G. R., Maple, H. J., Chan, V., Hall, A. J. & Hodgson, D. R. W. (2014). The Aqueous N-Phosphorylation and N-Thiophosphorylation of Aminonucleosides. RSC Advances 2014(73): 38663-38671.
• Joubert, Fanny, Musa, Osama M., Hodgson, David R. W. & Cameron, Neil R. (2014). The preparation of graft copolymers of cellulose and cellulose derivatives using ATRP under homogeneous reaction conditions. Chemical Society Reviews 43(20): 7217-7235.
• Korhonen, Heidi J., Conway, Louis P. & Hodgson, David R. W. (2014). Phosphate analogues in the dissection of mechanism. Current Opinion in Chemical Biology 21: 63-72.
• Trmčić, M., Chadbourne, F.L., Brear, P.M., Denny, P.W., Cobb, S.L. & Hodgson, D.R.W. (2013). Aqueous synthesis of N,S,-dialkylthiophosphoramidates: design, optimisation and application to library construction and antileishmanial testing. Organic and Biomolecular Chemistry 11(16): 2660-2675.
• Skipsey, M., Hack, G., Hooper, T. A., Shankey, M. C., Conway, L. P., Schröder, M. & Hodgson, D. R. W. (2013). 5’-Deoxy-5’-hydrazinylguanosine as an initiator of T7 RNA polymerase-catalyzed transcriptions for the preparation of labeling-ready RNAs. Nucleosides, Nucleotides, and Nucleic Acids 32(12): 670-681.
• Delley, R.J., Bandyopadhyay, S., Fox, M.A., Schliehe, C., Hodgson, D.R.W., Hollfelder, F., Kirby, A.J. & O'Donoghue, A.C. (2012). peri-Dimethylamino substituent effects on proton transfer at carbon in α-naphthylacetate esters: a model for mandelate racemase. Organic & Biomolecular Chemistry 10(3): 590-596.
• Delley, R.J., O'Donoghue, A.C. & Hodgson, D.R.W. (2012). Hydrolysis studies of phosphodichloridate and thiophosphodichloridate ions. The Journal of Organic Chemistry 77(13): 5829–5831.
• Hodgson, D.R.W. & Schröder, M. (2011). Chemical approaches towards unravelling kinase-mediated signalling pathways. Chemical Society Reviews 40(3): 1211-1223.
• Kwan, I.C.M. Delley, R.J., Hodgson, D.R.W. & Wu, G. (2011). Single atom modification leads to enhanced nucleotide self-assembly: the role of cation bridging. Chemical Communications 47(13): 3882-3884.
• Norcliffe, J.L., Conway, L.P. & Hodgson, D.R.W. (2011). Reduction of alkyl and aryl azides with sodium thiophosphate in aqueous solutions. Tetrahedron Letters 52(21): 2730-2732.
• Trmčić, M & Hodgson, DRW (2011). Synthesis of thiophosphoramidates in water: Click chemistry for phosphates. Chemical Communications 47(21): 6156-6158.
• Trmčić, M & Hodgson, D. R. W. (2010). Kinetic studies and predictions on the hydrolysis and aminolysis of esters of 2-S-phosphorylacetates. Beilstein Journal of Organic Chemistry 6: 732-741.
• Kirby, AJ, Davies, JE, Fox, DJ, Hodgson, DRW, Goeta, AE, Lima, MF, Priebe, JP, Santaballa, JA & Nome, F (2010). Ammonia oxide makes up some 20% of an aqueous solution of hydroxylamine. Chemical Communications 46(8): 1302-1304.
• Watson, H. R., Apperley, D. C., Dixon, D. P., Edwards, R. & Hodgson, D. R. W. (2009). An Efficient Method for ¹⁵N-Labeling of Chitin in Fungi. Biomacromolecules 10(4): 793-797.
• Brear, P, Freeman, GR Shankey, MC Trmčić, M & Hodgson, DRW (2009). Aqueous methods for the preparation of 5′-substituted guanosine derivatives. Chemical Communications 2009(33): 4980-4981.
• Townsend, PD, Holliday, PM, Fenyk, S, Hess, KC, Gray, MA, Hodgson, DRW & Cann, MJ (2009). Stimulation of Mammalian G-protein-responsive Adenylyl Cyclases by Carbon Dioxide. Journal Of Biological Chemistry 284(2): 784-791.
• Williamson, David & Hodgson, David R. W. (2008). Preparation and purification of 5 '-amino-5 '-deoxyguanosine-5 '-N-phosphoramidate and its initiation properties with T7 RNA polymerase. Organic & Biomolecular Chemistry 6(6): 1056-1062.
• Brazier-Hicks, M., Evans, K.M., Cunningham, O.D., Hodgson, D.R.W., Steel, P.G. & Edwards, R. (2008). Catabolism of glutathione conjugates in Arabidopsis thaliana: role in metabolic reactivation of the herbicide safener fenclorim. Journal of Biological Chemistry 283(30): 21102-21112.
• Williamson, D., Cann, M.J. & Hodgson, D.R.W. (2007). Synthesis of 5'-Amino-5'-deoxyguanosine-5'-N-phosphoramidate and its Enzymatic Incorporation at the 5'-Termini of RNA Molecules. Chemical Communications 2007(47): 5096-5098.
• Hammer, A., Hodgson, D.R.W. & Cann, M.J. (2006). Regulation of prokaryotic adenylyl cyclases by CO₂. Biochemical Journal 396(2): 215-218.
• N. Asaad, J. E. Davies, D. R. W. Hodgson, A. J. Kirby, L. van Vliet & L. Ottavi (2005). The search for efficient intramolecular proton transfer from carbon: the kinetically silent intramolecular general base-catalysed elimination reaction of O-phenyl 8-dimethylamino-1-naphthaldoximes. Journal of Physical Organic Chemistry 18(2): 101-109.
• D. R. W. Hodgson & H. Suga (2004). Mechanistic studies on acyl-transferase ribozymes and beyond. Biopolymers 73(1): 130-150.
• Hodgson, D. R. W. & Sanderson, J. M. (2004). The Synthesis of Peptides and Proteins Containing Non-Natural Amino Acids. Chemical Society Reviews 33(7): 422-430.
• B. G. Davis, R. F. Sala, D. R. W. Hodgson, A. Ullman, K. Khumtaveeporn, D. A. Estell, K. Sanford, R. R. Bott & J. B. Jones (2003). Selective protein degradation by ligand-targeted enzymes: towards the creation of catalytic antagonists. ChemBioChem 4(6): 533-537.
• Y. Bessho, D. R. W. Hodgson & H. Suga (2002). A tRNA aminoacylation system for non-natural amino acids based on a programmable ribozyme. Nature Biotechnology 20(7): 723-728.
• Hartwell, E., Hodgson, D. R. W. & Kirby, A. J. (2000). Exploring the limits of efficiency of proton-transfer catalysis in models and enzymes. Journal of the American Chemical Society 122(38): 9326-9327.
• Hodgson, D. R. W., Kirby, A. J. & Feeder, N. (1999). The case of the missing acetylene. The mechanism of an intramolecular S-N(V) reaction and a new route to 1-methylbenzo[de]quinolines. Journal of the Chemical Society, Perkin Transactions 1 (8): 949-954.
• GenreGrandpierre, A., Tellier, C., Loirat, M. J., Blanchard, D., Hodgson, D. R. W., Hollfelder, F. & Kirby, A. J. (1997). Catalysis of the Kemp elimination by antibodies elicited against a cationic hapten. Bioorganic & Medicinal Chemistry Letters 7(19): 2497-2502.
• Colbert, M. C. B., Hodgson, D., Lewis, J., Raithby, P. R. & Long, N. J. (1995). Synthesis, Characterization and Electrochemical Studies of 1',6'-Bis(Ethynyl)Biferrocene and Some Metal-Complexes - Novel Heterometallic Compounds Towards Nonlinear Optics. Polyhedron 14(19): 2759-2766.

Patent

• David Hodgson (2020). TRIPHOSPHORYLATION REACTION. WO 2020/008209A1. Application filed: 5 July 2019. Granted: 9 January 2020