The synthesis of potential inhibitors of renin and pepsin
The synthesis of potential inhibitors of renin and pepsin
Analogues of the acid protease inhibitor, pepstatin (9), have been synthesised and tested for inhibitory effectiveness against pepsin. Analogues in which the C-3 hydroxyl group of statine has been replaced by an amine moiety (30 and 31), displayed inhibitory activity but were some 100 times less effective than analogous compounds containing the C-3 hydroxyl group (32 and 33). When the peptide bond between statine and alanine, in pepstatin analogues, is replaced with a simple secondary amine, the resulting amino-alcohol containing compounds (38 and 39) are very poor inhibitors of pepsin when compared to both the parent pepstatin analogues (40 and 41) and the aminostatine containing compounds (30 and 31). When the tertbutoxycarbonyl protecting group is removed from these amino-alcohols, the resultant compounds contain both a primary and a secondary amine moiety (42 and 43) but do not inhibit pepsin at all. Research conducted elsewhere has shown that compounds containing the aminostatine residue in the (3R) configuration are more effective inhibitors of the acid proteases, renin and endothiapepsin, than pepstatin analogues which bear the same (3R) configuration and deshydroxypepstatin. This is thought to be due to a long range ionic interaction which exists in the (3R) aminopepstatin analogue-enzyme complex, but which the (3R) pepstatin- and deshydroxypepstatin-enzyme complexes cannot undergo. This same research has also shown that compounds which contain the aminostatine residue and compounds which contain the amino-alcohol moiety, are as effective inhibitors of renin and endothiapepsin as pepstatin analogues. It is therefore concluded that these types of compound experience some repulsion from the active site of pepsin which they do not experience with other acid proteases. Possible reasons for this are discussed. (D71562/87)
University of Southampton
1986
Lister, Phillip Mark
(1986)
The synthesis of potential inhibitors of renin and pepsin.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
Analogues of the acid protease inhibitor, pepstatin (9), have been synthesised and tested for inhibitory effectiveness against pepsin. Analogues in which the C-3 hydroxyl group of statine has been replaced by an amine moiety (30 and 31), displayed inhibitory activity but were some 100 times less effective than analogous compounds containing the C-3 hydroxyl group (32 and 33). When the peptide bond between statine and alanine, in pepstatin analogues, is replaced with a simple secondary amine, the resulting amino-alcohol containing compounds (38 and 39) are very poor inhibitors of pepsin when compared to both the parent pepstatin analogues (40 and 41) and the aminostatine containing compounds (30 and 31). When the tertbutoxycarbonyl protecting group is removed from these amino-alcohols, the resultant compounds contain both a primary and a secondary amine moiety (42 and 43) but do not inhibit pepsin at all. Research conducted elsewhere has shown that compounds containing the aminostatine residue in the (3R) configuration are more effective inhibitors of the acid proteases, renin and endothiapepsin, than pepstatin analogues which bear the same (3R) configuration and deshydroxypepstatin. This is thought to be due to a long range ionic interaction which exists in the (3R) aminopepstatin analogue-enzyme complex, but which the (3R) pepstatin- and deshydroxypepstatin-enzyme complexes cannot undergo. This same research has also shown that compounds which contain the aminostatine residue and compounds which contain the amino-alcohol moiety, are as effective inhibitors of renin and endothiapepsin as pepstatin analogues. It is therefore concluded that these types of compound experience some repulsion from the active site of pepsin which they do not experience with other acid proteases. Possible reasons for this are discussed. (D71562/87)
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Published date: 1986
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Local EPrints ID: 460720
URI: http://eprints.soton.ac.uk/id/eprint/460720
PURE UUID: dc512632-03cb-4c70-8bbf-2a88e293834b
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Date deposited: 04 Jul 2022 18:28
Last modified: 04 Jul 2022 18:28
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Author:
Phillip Mark Lister
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