Comparison of the mechanisms of reactions of β lactams and β-sultams, including their reactions with some serine enzymes

Michael I. Page, Wing Y. Tsang, Naveed Ahmed

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The strain energy of the four-membered ring of β-lactams is not released in the transition state to lower the activation energy of reactions involving ring-opening. The alkaline hydrolysis of N-aroyl β-lactams occurs with competitive exo- and endocyclic C - N ring fission, the ratio of which varies with the aryl substituent. β-Sultams are four-membered cyclic sulfonamides and are about 103 fold more reactive than analogous β-lactams. Nucleophiles usually attack N-acylsulfonamides at the carbonyl centre resulting in C - N bond fission, but the hydrolysis of N-acyl β-sultams occurs with S -N fission and opening of the four-membered ring. The 3-oxo-β-sultams are a unique combination of both β-lactams and β-sultams and therefore are susceptible to nucleophilic attack at either the acyl or the sulfonyl centre, but they hydrolyse with exclusive S - N bond fission. β-Sultams are novel inhibitors of the serine enzymes elastase, transpeptidase and β-lactamase due to sulfonylation of the active-site serine residue. Structure-activity relationships are used to identify differences in transition-state structures between β-sultams as inhibitors and β-lactams as substrates.

LanguageEnglish
Pages446-451
Number of pages6
JournalJournal of Physical Organic Chemistry
Volume19
Issue number8-9
Early online date30 Jan 2006
DOIs
Publication statusPublished - Aug 2006

Fingerprint

beta-Lactams
Serine
fission
enzymes
rings
Enzymes
inhibitors
attack
hydrolysis
Hydrolysis
nucleophiles
Peptidyl Transferases
Nucleophiles
Pancreatic Elastase
Sulfonamides
beta-Lactamases
activation energy
Strain energy
beta-sultam
Activation energy

Cite this

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abstract = "The strain energy of the four-membered ring of β-lactams is not released in the transition state to lower the activation energy of reactions involving ring-opening. The alkaline hydrolysis of N-aroyl β-lactams occurs with competitive exo- and endocyclic C - N ring fission, the ratio of which varies with the aryl substituent. β-Sultams are four-membered cyclic sulfonamides and are about 103 fold more reactive than analogous β-lactams. Nucleophiles usually attack N-acylsulfonamides at the carbonyl centre resulting in C - N bond fission, but the hydrolysis of N-acyl β-sultams occurs with S -N fission and opening of the four-membered ring. The 3-oxo-β-sultams are a unique combination of both β-lactams and β-sultams and therefore are susceptible to nucleophilic attack at either the acyl or the sulfonyl centre, but they hydrolyse with exclusive S - N bond fission. β-Sultams are novel inhibitors of the serine enzymes elastase, transpeptidase and β-lactamase due to sulfonylation of the active-site serine residue. Structure-activity relationships are used to identify differences in transition-state structures between β-sultams as inhibitors and β-lactams as substrates.",
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Comparison of the mechanisms of reactions of β lactams and β-sultams, including their reactions with some serine enzymes. / Page, Michael I.; Tsang, Wing Y.; Ahmed, Naveed.

In: Journal of Physical Organic Chemistry, Vol. 19, No. 8-9, 08.2006, p. 446-451.

Research output: Contribution to journalArticle

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