The synthesis and evaluation of potential transglutaminase inhibitors

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Saint, R.E., 1998. The synthesis and evaluation of potential transglutaminase inhibitors. PhD, Nottingham Trent University.

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Abstract

Transglutaminases are a group of widely distributed enzymes which catalyse the post-transitional modification of proteins by covalent cross-linking of protein- bound glutamine residues with primary amines.

A number of transglutaminase inhibitors have been previously developed to assist in the investigation of transglutaminases in biological processes, but many are non-selective, toxic to whole cells or insoluble in biological media. The aim of the present research was to improve the synthesis of some of the best known inhibitors and to develop new compounds with improved potency, selectivity and solubility in minimally toxic media.

The main area of research centred on known inhibitors derived from N-benzyloxycarbonyl-L-phenylalanine. Existing preparations of these compounds necessitate the use hazardous diazomethane. Novel synthetic routes to these compounds which avoided the use of this reagent were established. In particular a short route to 6-diazo-5-oxo-L-norleucine (DON) (22) a key intermediate was developed, involving low temperature ring-opening of N-protected pyroglutamates by lithium trimethylsilyldiazomethane; a summary of this work has been published. The ring-opening has also been applied to the preparation of protected 2-aminoadipates.

An alternative approach to related chloromethyl ketone inhibitors by the reaction of pyroglutamates with halogeno-esters and lithium chloromethyltrimethyl-silane was only partially successful, but gave rise to interesting by-products.

Potential irreversible inhibitors, containing vinyl sulfone or α,β-unsaturated ester electrophilic sites, not previously used in transglutaminase inhibitors, were prepared in short synthetic sequences again using ring-opening of γ-lactams.

These last compounds showed no inhibitory activity, but a number of the earlier compounds were active with IC50 values of less than 500?M. The most promising compound, a Z-phenylalanyl sulfonium bromide (56) has an IC50 value of approximately l00?M, is water soluble eind of low toxicity, comparable with mercaptoimidazole 7, a known good transglutaminase inhibitor.

Item Type:

Thesis

Creators:

Saint, R.E.

Date:

1998

ISBN:

9781369323634

Identifiers: