Reactivity of β-lactams and phosphonamidates and reactions with β-lactamase

M. I. Page, A. P. Laws, M. J. Slater, J. R. Stone

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Thermodynamically strained four membered cyclic β -lactams do not show a corresponding kinetic effect in the rates of their ring opening reactions. Contrary to expectations, breaking the C-N bond in these strained ring structures appears to be a relatively difficult process. A four membered cyclic phosphonamidate, on the other hand, undergoes rapid hydrolysis in water with exclusive endocyclic P-N fission with a rate difference, compared with an acyclic analogue, of greater than 5x108. Two diastereoisomers of a phosphonamidate completely and irreversibly inactivate the class C β -lactamase (P99) from Enterobacter cloacae in a time dependent manner. There is diastereoselectivity shown by the two inactivators and the more active one has proline displaced by the enzyme. Protonation of the phosphonamidate nitrogen is almost certainly required to expel neutral proline. Effective enzyme catalysed phosphonylation is surprising in view of the presumed different geometries for the reaction (trigonal bipyramidal) compared with that for acylation (tetrahedral).

LanguageEnglish
Pages711-717
Number of pages7
JournalPure and Applied Chemistry
Volume67
Issue number5
DOIs
Publication statusPublished - 1 Jan 1995

Fingerprint

beta-Lactams
beta-Lactamases
Proline
Enzymes
Acylation
Protonation
Hydrolysis
Nitrogen
Kinetics
Geometry
Water
Lactams

Cite this

Page, M. I. ; Laws, A. P. ; Slater, M. J. ; Stone, J. R. / Reactivity of β-lactams and phosphonamidates and reactions with β-lactamase. In: Pure and Applied Chemistry. 1995 ; Vol. 67, No. 5. pp. 711-717.
@article{fb34867c652c484abeb76427c19d813f,
title = "Reactivity of β-lactams and phosphonamidates and reactions with β-lactamase",
abstract = "Thermodynamically strained four membered cyclic β -lactams do not show a corresponding kinetic effect in the rates of their ring opening reactions. Contrary to expectations, breaking the C-N bond in these strained ring structures appears to be a relatively difficult process. A four membered cyclic phosphonamidate, on the other hand, undergoes rapid hydrolysis in water with exclusive endocyclic P-N fission with a rate difference, compared with an acyclic analogue, of greater than 5x108. Two diastereoisomers of a phosphonamidate completely and irreversibly inactivate the class C β -lactamase (P99) from Enterobacter cloacae in a time dependent manner. There is diastereoselectivity shown by the two inactivators and the more active one has proline displaced by the enzyme. Protonation of the phosphonamidate nitrogen is almost certainly required to expel neutral proline. Effective enzyme catalysed phosphonylation is surprising in view of the presumed different geometries for the reaction (trigonal bipyramidal) compared with that for acylation (tetrahedral).",
author = "Page, {M. I.} and Laws, {A. P.} and Slater, {M. J.} and Stone, {J. R.}",
year = "1995",
month = "1",
day = "1",
doi = "10.1351/pac199567050711",
language = "English",
volume = "67",
pages = "711--717",
journal = "Pure and Applied Chemistry",
issn = "0033-4545",
publisher = "IUPAC Secretariat",
number = "5",

}

Reactivity of β-lactams and phosphonamidates and reactions with β-lactamase. / Page, M. I.; Laws, A. P.; Slater, M. J.; Stone, J. R.

In: Pure and Applied Chemistry, Vol. 67, No. 5, 01.01.1995, p. 711-717.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Reactivity of β-lactams and phosphonamidates and reactions with β-lactamase

AU - Page, M. I.

AU - Laws, A. P.

AU - Slater, M. J.

AU - Stone, J. R.

PY - 1995/1/1

Y1 - 1995/1/1

N2 - Thermodynamically strained four membered cyclic β -lactams do not show a corresponding kinetic effect in the rates of their ring opening reactions. Contrary to expectations, breaking the C-N bond in these strained ring structures appears to be a relatively difficult process. A four membered cyclic phosphonamidate, on the other hand, undergoes rapid hydrolysis in water with exclusive endocyclic P-N fission with a rate difference, compared with an acyclic analogue, of greater than 5x108. Two diastereoisomers of a phosphonamidate completely and irreversibly inactivate the class C β -lactamase (P99) from Enterobacter cloacae in a time dependent manner. There is diastereoselectivity shown by the two inactivators and the more active one has proline displaced by the enzyme. Protonation of the phosphonamidate nitrogen is almost certainly required to expel neutral proline. Effective enzyme catalysed phosphonylation is surprising in view of the presumed different geometries for the reaction (trigonal bipyramidal) compared with that for acylation (tetrahedral).

AB - Thermodynamically strained four membered cyclic β -lactams do not show a corresponding kinetic effect in the rates of their ring opening reactions. Contrary to expectations, breaking the C-N bond in these strained ring structures appears to be a relatively difficult process. A four membered cyclic phosphonamidate, on the other hand, undergoes rapid hydrolysis in water with exclusive endocyclic P-N fission with a rate difference, compared with an acyclic analogue, of greater than 5x108. Two diastereoisomers of a phosphonamidate completely and irreversibly inactivate the class C β -lactamase (P99) from Enterobacter cloacae in a time dependent manner. There is diastereoselectivity shown by the two inactivators and the more active one has proline displaced by the enzyme. Protonation of the phosphonamidate nitrogen is almost certainly required to expel neutral proline. Effective enzyme catalysed phosphonylation is surprising in view of the presumed different geometries for the reaction (trigonal bipyramidal) compared with that for acylation (tetrahedral).

UR - http://www.scopus.com/inward/record.url?scp=0001487950&partnerID=8YFLogxK

U2 - 10.1351/pac199567050711

DO - 10.1351/pac199567050711

M3 - Article

VL - 67

SP - 711

EP - 717

JO - Pure and Applied Chemistry

T2 - Pure and Applied Chemistry

JF - Pure and Applied Chemistry

SN - 0033-4545

IS - 5

ER -