skip to content
 

Dr Finian Leeper

Portrait of fjl1

Coenzyme Chemistry

Thiamin diphosphate (TPP) 1 is a coenzyme used by many enzymes which make and break bonds adjacent to keto groups. We have synthesised deaza analogues (e.g. 2) of intermediates in these reactions. These bind extremely tightly to TPP-dependent enzymes. We aim to make further analogues that are inhibitors of specific enzymes and may thus be of medicinal importance. We also hope to get crystal structures of the analogues bound to their target enzymes which should help to understand how the reactions occur.

Novel Catalysts

Thiazolium salts catalyse a variety of reactions involving making and breaking bonds to a carbonyl carbon (e.g. the benzoin condensation). We have made chiral thiazolium salts (e.g. 3) and have observed asymmetric induction in formation of benzoin. We intend to further develop these catalysts to obtain better levels of asymmetric induction, to probe the mechanism and to introduce binding cavities for increased rate and better selectivities.

Enzyme Chemistry

A key step in tetrapyrrole biosynthesis is the linking of four molecules of the monopyrrole PBG (4) to give a linear tetrapyrrole, catalysed by PBG deaminase. A crystal structure is available and we plan to use this to design and then synthesise analogues of PBG which bind tightly to the enzyme. These will aid understanding of the mechanism and may be of value as antibiotics and/or herbicides.

Biosynthesis of Prodigiosin

(with Prof G. Salmond, Biochemistry) Prodigiosin (see below) is an immunosuppressant with a novel mode of action. We have found the cluster of genes that codes for its biosynthesis in Serratia marcescens and are working on the elucidation of the biosynthetic pathway and the mechanisms of the enzymic reactions involved.

Synthetic Methods for PET

(with Dr F. Aigbirhio, Wolfson Brain Imaging Centre) Positron Emission Tomography (PET) is a technique used for scanning human brain to detect the distribution of compounds of diagnostic interest. It relies on compounds labelled with very short- lived radioisotopes (e.g. 11C or 18F). The whole synthesis of such compounds must not take longer than ~30 mins. The aim of this project is to develop new synthetic methods, using polymer-supported reagents, that will allow such rapid synthesis and isolation of labelled compounds of neuropharmacological importance.

Publications

Structure of a eukaryotic thiaminase I.
CA Kreinbring, SP Remillard, P Hubbard, HR Brodkin, FJ Leeper, D Hawksley, EY Lai, C Fulton, GA Petsko, D Ringe – Proceedings of the National Academy of Sciences of the United States of America (2014) 111, 137
Dual-sugar imaging using isonitrile and azido-based click chemistries
YA Wainman, AA Neves, S Stairs, H Stöckmann, H Ireland-Zecchini, KM Brindle, FJ Leeper – Org Biomol Chem (2013) 11, 7297
Sub-angstrom-resolution crystallography reveals physical distortions that enhance reactivity of a covalent enzymatic intermediate.
S Lüdtke, P Neumann, KM Erixon, F Leeper, R Kluger, R Ficner, K Tittmann – Nature Chemistry (2013) 5, 762
Imaging cell surface glycosylation in vivo using "double click" chemistry.
AA Neves, H Stöckmann, YA Wainman, JC Kuo, S Fawcett, FJ Leeper, KM Brindle – Bioconjugate Chemistry (2013) 24, 934
alpha-Hydroxy-beta-keto acid rearrangement-decarboxylation: impact on thiamine diphosphate-dependent enzymatic transformations
M Beigi, S Loschonsky, P Lehwald, V Brecht, SL Andrade, FJ Leeper, W Hummel, M Müller – Org Biomol Chem (2013) 11, 252
Metabolic glycan imaging by isonitrile-tetrazine click chemistry
S Stairs, AA Neves, H Stöckmann, YA Wainman, H Ireland-Zecchini, KM Brindle, FJ Leeper – ChemBioChem (2013) 14, 1063
Bacterial Biosynthetic Gene Clusters Encoding the Anti-cancer Haterumalide Class of Molecules BIOGENESIS OF THE BROAD SPECTRUM ANTIFUNGAL AND ANTI-OOMYCETE COMPOUND, OOCYDIN A
MA Matilla, H Stöckmann, FJ Leeper, GP Salmond – J Biol Chem (2012) 287, 39125
Probing riboswitch-ligand interactions using thiamine pyrophosphate analogues.
L Chen, E Cressina, N Dixon, K Erixon, K Agyei-Owusu, J Micklefield, AG Smith, C Abell, FJ Leeper – Org Biomol Chem (2012) 10, 5924
Characterisation of PigC and HapC, the prodigiosin synthetases from Serratia sp and Hahella chejuensis with potential for biocatalytic production of anticancer agents
SR Chawrai, NR Williamson, T Mahendiran, GPC Salmond, FJ Leeper – Chemical Science (2012) 3, 447
Copper-free click - A promising tool for pre-targeted PET imaging
HL Evans, RL Slade, L Carroll, G Smith, QD Nguyen, L Iddon, N Kamaly, H Stöckmann, FJ Leeper, EO Aboagye, AC Spivey – Chemical communications (Cambridge, England) (2012) 48, 991
  •  
  • 1 of 13
  • >

Research Group

Research Interest Group

Telephone number

01223 336403

Email address

fjl1@cam.ac.uk