Research Projects
- Inhibitors of the Pantothenate Pathway
- Investigation into ‘Merged Substitution-Elimination’ Reactions
- Peptide Mimics with Potential Non-addictive Analgesic Properties
1. Inhibitors of the Pantothenate Pathway
 Pantothenate (otherwise known as Vitamin B 5) is a key precursor for the biosynthesis of coenzyme A (CoA) and acyl carrier protein (ACP). Both of these are necessary cofactors for cell growth and are involved in essential biosynthetic pathways. The pantothenate pathway is comprised of four enzymatic reactions. As this pathway is not present in mammals it represents an exciting target for the development of novel antibiotics and herbicides.
This project will involve the synthesis of inhibitors of pantothenate synthetase, the last enzyme in the pantothenate pathway. Pantothenate synthetase is a member of the aminoacyl-tRNA synthetase superfamily, and involves the formation of an acyl adenylate intermediate in its mechanism. Previous work has shown that replacement of the labile phosphate ester with a stable non-hydrolysable sulfonamide group results in inhibitors which are active at concentrations below one micromolar.
2. Investigation into ‘Merged Substitution-Elimination’ Reactions
 Good nucleophiles which are weak bases are known to undergo substitution reactions in preference to elimination reactions. During the synthesis of a pheromone 2 of the Douglas-fir beetle (d endroctonus pseudotsugae ) it was discovered that reaction of the tosylate 2 with phenyl selenide anion, a good nucleophile, surprisingly gave the eliminated product 1 directly (Scheme 1). Whereas potassium t–butoxide, a strong base and poor nucleophile, abstracted the hydroxyl proton from the tosylate 2 to giverearrangement products 3 and 4. The question arises as to why selenide anion, a powerful nucleophile to carbon but non-nucleophilic to hydrogen attached to the oxygen of an alcohol, should suddenly change allegiance and abstract a hydrogen attached to carbon. This reaction was termed a ‘merged-substitution elimination’ reaction and was first mentioned in 1956, but there have been no other examples of this reaction until recently.
 A study of models shows that the nucleophile, the reaction centre and the leaving group can stay co-linear throughout the reaction (Figure 1). There is an obstacle to rear-side attack and the deflected nucleophile could then abstract the hydrogen atom. Numerous analogues of the tosylate 2 will be synthesised and the requirements required for this interesting ‘merged substitution-elimination reaction’ will be investigated.
3. Peptide Mimics with Potential Non-addictive Analgesic Properties
(Collaboration with Peter Duggan, CSIRO)
 This project involves further development of peptide mimics of the cone shell toxin, w -conatoxin GVIA, a small cystine knot which binds tightly to neuronal N-type calcium channels. GVIA has non-addictive analgesic properties but is not suitable for use as a drug because of its very strong binding to the calcium channel. In addition, it suffers from the usual unfavorable characteristics associated with peptides such as low bio-availability and susceptibility to proteolysis. Peptide mimics have the potential to overcome these problems. The two classes of mimics that we are studying possess three amino acid side chain analogues projecting from semi-rigid scaffolds. These structures have been designed with the aid of molecular modeling and aim to simulate the way three key amino acid side chains of GVIA are presented to the receptor. Lead compounds have been tested and show promising activity.
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