Latent inhibitors. Part 9. substrate activated time-dependent inhibition of carboxypeptidase a by aminocyclopropanecarboxylic acid derivatives and analogues

Alison Kemp, Surjit K. Ner, Lilias Rees, Colin J. Suckling, M. Catriona Tedford, Andrew R. Bell, Roger Wrigglesworth

Research output: Contribution to journalArticle

Abstract

A series of 1-aminocyclopropanecarboxylic acid derivatives and analogues have been synthesised as potential inhibitors of carboxypeptidase A. Whereas simple cyclopropylcarboxamido derivatives of Gly, Phe and Pro showed no indications of time-dependent, irreversible inhibition, benzamido-1-aminocyclopropane carboxamido-Phe and Pro were characterised as latent inhibitors. The former was also a substrate for carboxypeptidase A but the latter was purely an inhibitor. This behaviour suggested that cyclopropylketones should also be inhibitors of carboxypeptidase A; this suggestion was confirmed experimentally. Kinetic experiments showed surprisingly that the rate of inhibition is increased in the presence of substrate, hippurylphenylalanine. Related secondary alcohols also acted as time-dependent inhibitors. The results are evaluated in the context of current views on the mechanism of action of carboxypeptidase A.
Original languageEnglish
Pages (from-to)741-748
Number of pages8
JournalJournal of the Chemical Society, Perkin Transactions 2
Volume1993
Issue number4
DOIs
Publication statusPublished - Apr 1993

Cite this

@article{270af2b7334e4d1d90d9a42941657a69,
title = "Latent inhibitors. Part 9.: substrate activated time-dependent inhibition of carboxypeptidase a by aminocyclopropanecarboxylic acid derivatives and analogues",
abstract = "A series of 1-aminocyclopropanecarboxylic acid derivatives and analogues have been synthesised as potential inhibitors of carboxypeptidase A. Whereas simple cyclopropylcarboxamido derivatives of Gly, Phe and Pro showed no indications of time-dependent, irreversible inhibition, benzamido-1-aminocyclopropane carboxamido-Phe and Pro were characterised as latent inhibitors. The former was also a substrate for carboxypeptidase A but the latter was purely an inhibitor. This behaviour suggested that cyclopropylketones should also be inhibitors of carboxypeptidase A; this suggestion was confirmed experimentally. Kinetic experiments showed surprisingly that the rate of inhibition is increased in the presence of substrate, hippurylphenylalanine. Related secondary alcohols also acted as time-dependent inhibitors. The results are evaluated in the context of current views on the mechanism of action of carboxypeptidase A.",
author = "Alison Kemp and Ner, {Surjit K.} and Lilias Rees and Suckling, {Colin J.} and Tedford, {M. Catriona} and Bell, {Andrew R.} and Roger Wrigglesworth",
year = "1993",
month = "4",
doi = "10.1039/P29930000741",
language = "English",
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pages = "741--748",
journal = "Journal of the Chemical Society, Perkin Transactions 2",
issn = "1472-779X",
publisher = "Royal Society of Chemistry",
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}

Latent inhibitors. Part 9. substrate activated time-dependent inhibition of carboxypeptidase a by aminocyclopropanecarboxylic acid derivatives and analogues. / Kemp, Alison; Ner, Surjit K.; Rees, Lilias; Suckling, Colin J.; Tedford, M. Catriona; Bell, Andrew R.; Wrigglesworth, Roger.

In: Journal of the Chemical Society, Perkin Transactions 2, Vol. 1993, No. 4, 04.1993, p. 741-748.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Latent inhibitors. Part 9.

T2 - substrate activated time-dependent inhibition of carboxypeptidase a by aminocyclopropanecarboxylic acid derivatives and analogues

AU - Kemp, Alison

AU - Ner, Surjit K.

AU - Rees, Lilias

AU - Suckling, Colin J.

AU - Tedford, M. Catriona

AU - Bell, Andrew R.

AU - Wrigglesworth, Roger

PY - 1993/4

Y1 - 1993/4

N2 - A series of 1-aminocyclopropanecarboxylic acid derivatives and analogues have been synthesised as potential inhibitors of carboxypeptidase A. Whereas simple cyclopropylcarboxamido derivatives of Gly, Phe and Pro showed no indications of time-dependent, irreversible inhibition, benzamido-1-aminocyclopropane carboxamido-Phe and Pro were characterised as latent inhibitors. The former was also a substrate for carboxypeptidase A but the latter was purely an inhibitor. This behaviour suggested that cyclopropylketones should also be inhibitors of carboxypeptidase A; this suggestion was confirmed experimentally. Kinetic experiments showed surprisingly that the rate of inhibition is increased in the presence of substrate, hippurylphenylalanine. Related secondary alcohols also acted as time-dependent inhibitors. The results are evaluated in the context of current views on the mechanism of action of carboxypeptidase A.

AB - A series of 1-aminocyclopropanecarboxylic acid derivatives and analogues have been synthesised as potential inhibitors of carboxypeptidase A. Whereas simple cyclopropylcarboxamido derivatives of Gly, Phe and Pro showed no indications of time-dependent, irreversible inhibition, benzamido-1-aminocyclopropane carboxamido-Phe and Pro were characterised as latent inhibitors. The former was also a substrate for carboxypeptidase A but the latter was purely an inhibitor. This behaviour suggested that cyclopropylketones should also be inhibitors of carboxypeptidase A; this suggestion was confirmed experimentally. Kinetic experiments showed surprisingly that the rate of inhibition is increased in the presence of substrate, hippurylphenylalanine. Related secondary alcohols also acted as time-dependent inhibitors. The results are evaluated in the context of current views on the mechanism of action of carboxypeptidase A.

U2 - 10.1039/P29930000741

DO - 10.1039/P29930000741

M3 - Article

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JO - Journal of the Chemical Society, Perkin Transactions 2

JF - Journal of the Chemical Society, Perkin Transactions 2

SN - 1472-779X

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