Synthetic studies towards a novel reverse turn peptidomimetic
Synthetic studies towards a novel reverse turn peptidomimetic
The synthesis of novel, conformationally constrained α-amino acids for use in exploring the relationship between peptide structure and function remains an active area of research interest. Highly functionalised analogues of glutamates, aspartates, and prolines, have potential application in probing the active site of enzymes involved in amino acid catalysis, and may prove useful as precursors from peptidomimetics. The current synthetic approaches for the construction of these molecules are reviewed, and examples of their uses in probing features of biological systems are briefly discussed. In addition, the preparation of highly functionalised derivatives of many peptidomimetics remains to be accomplished, given the inflexibility of the routes used to obtain the parent compounds. We have investigated the utility of using simple alkylations of L-aspartic acid followed by routine transformations to yield functionalised peptidomimetics and a series of novel α-amino acid analogues.
In our initial studies, we have shown for the first time that the diastereoselectivity of the β-alkylation reaction can be controlled by simple manipulation of the reaction conditions for a range of electrophiles, and we have systematically studied the effects of temperature, ionic strength and leaving group reactivity in determining the stereochemical outcome of this reaction. The extension of this work to the synthesis of novel β-functionalised amino acids has also been investigated, and a stereospecific route to 3-substituted prolines developed. Furthermore, several novel analogues of aspartic and glutamic acid have been assayed as inhibitors of asparagine synthetase (AS), an enzyme which mediates the biosynthesis of asparagine in the liver cells, and the results are discussed. Of particular interest is the finding that (2S,3R)-2-amino-succinic acid is a competitive inhibitor of asparagine synthetase (AS) at millimolar concentrations. Hence, this compound represents the first albeit weak, inhibitor which has been kinetically characterised.
University of Southampton
1994
Parr, Ian Barrie
(1994)
Synthetic studies towards a novel reverse turn peptidomimetic.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
The synthesis of novel, conformationally constrained α-amino acids for use in exploring the relationship between peptide structure and function remains an active area of research interest. Highly functionalised analogues of glutamates, aspartates, and prolines, have potential application in probing the active site of enzymes involved in amino acid catalysis, and may prove useful as precursors from peptidomimetics. The current synthetic approaches for the construction of these molecules are reviewed, and examples of their uses in probing features of biological systems are briefly discussed. In addition, the preparation of highly functionalised derivatives of many peptidomimetics remains to be accomplished, given the inflexibility of the routes used to obtain the parent compounds. We have investigated the utility of using simple alkylations of L-aspartic acid followed by routine transformations to yield functionalised peptidomimetics and a series of novel α-amino acid analogues.
In our initial studies, we have shown for the first time that the diastereoselectivity of the β-alkylation reaction can be controlled by simple manipulation of the reaction conditions for a range of electrophiles, and we have systematically studied the effects of temperature, ionic strength and leaving group reactivity in determining the stereochemical outcome of this reaction. The extension of this work to the synthesis of novel β-functionalised amino acids has also been investigated, and a stereospecific route to 3-substituted prolines developed. Furthermore, several novel analogues of aspartic and glutamic acid have been assayed as inhibitors of asparagine synthetase (AS), an enzyme which mediates the biosynthesis of asparagine in the liver cells, and the results are discussed. Of particular interest is the finding that (2S,3R)-2-amino-succinic acid is a competitive inhibitor of asparagine synthetase (AS) at millimolar concentrations. Hence, this compound represents the first albeit weak, inhibitor which has been kinetically characterised.
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Published date: 1994
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Local EPrints ID: 458600
URI: http://eprints.soton.ac.uk/id/eprint/458600
PURE UUID: 66c2df0f-b45e-4e3d-8657-c631f0f1535a
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Date deposited: 04 Jul 2022 16:52
Last modified: 04 Jul 2022 16:52
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Author:
Ian Barrie Parr
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