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.
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.
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.
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