Structure–reactivity relationships in the inactivation of elastase by β-sultams

Hinchliffe, Paul S.; Wood, J. Matthew; Davis, Andrew M.; Austin, Rupert P.; Beckett, R.Paul; Page, Michael I.

doi:10.1039/b208079f

Cited by 40 publications

(40 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…22, 23 The inhibition of elastase by monocyclic b-lactams has also been improved by the introduction of alkyl substituents at the 3-position, which are thought to bind strongly in the S 1 subsite of elastase. 24, 25 We therefore wished to investigate any differential effects of these substituents on chemical reactivity and enzyme binding.…”

Section: Methodsmentioning

confidence: 99%

Reactivity and selectivity in the inhibition of elastase by 3-oxo-β-sultams and in their hydrolysis

et al. 2007

Self Cite

View full text Add to dashboard Cite

3-oxo-beta-sultams are both beta-sultams and beta-lactams and are a novel class of time-dependent inhibitors of elastase. The inhibition involves formation of a covalent enzyme-inhibitor adduct with transient stability by acylation of the active-site serine resulting from substitution at the carbonyl centre of the 3-oxo-beta-sultam, C-N fission, and expulsion of the sulfonamide. The lead compound, N-benzyl-4,4-dimethyl-3-oxo-beta-sultam 1 is a reasonably potent inhibitor against porcine pancreatic elastase with a second-order rate constant of 768 M(-1) s(-1) at pH 6, but also possesses high chemical reactivity with a half-life for hydrolysis of only 6 mins at the same pH in water. Interestingly, the hydrolysis of 3-oxo-beta-sultams occurs at the sulfonyl centre with S-N fission and expulsion of the amide leaving group, whereas the enzyme reaction occurs at the acyl centre. Increasing selectivity between these two reactive centres was explored by examining the effect of substituents on the reactivity of 3-oxo-beta-sultam towards hydrolysis and enzyme inhibition. The inhibition activity against porcine pancreatic elastase has a much higher sensitivity to substituent variation than does the rate of alkaline hydrolysis. A difference of 2000-fold is observed in the second-order rate constants, k(i), for inhibition whereas there is only a 100-fold difference in the second-order rate constants, k(OH), for alkaline hydrolysis within the series. The higher sensitivity of enzyme inhibition to substituents than that of simple chemical reactivity indicates a significant degree of molecular recognition of the 3-oxo-beta-sultams by the enzyme.

show abstract

Section: Methodsmentioning

confidence: 99%

Reactivity and selectivity in the inhibition of elastase by 3-oxo-β-sultams and in their hydrolysis

et al. 2007

Self Cite

View full text Add to dashboard Cite

show abstract

“…β‐Sultams can act as irreversible active‐site‐directed inhibitors of elastases such as the human neutrophil elastase , β‐lactamase , and D,D ‐peptidase inhibitors . The anti‐inflammatory roles of these compounds have also been reported .…”

Section: Introductionmentioning

confidence: 99%

A Simple and One‐Pot Synthesis of β‐Sultams by Using the Vilsmeier Reagent

Zarei

Jarrahpour

2013

Journal of Heterocyclic Chem

View full text Add to dashboard Cite

“…Page and his coworkers have done many studies from experiment. [4][5][6][7][8][9] Within this scope, in previous work we have presented theoretical studies with and without participation of water alcoholysis for 1,2-thiazetidine 1,1-dioxides as models of biological hydrolysis of β-sultams. [10][11][12] In the present study, the polarized continuum model (PCM) within the framework of the self-consistent reaction field (SCRF) theory, which has been quite successful in describing the solvent (water) effects on the reaction, [14][15][16] has been used to model the continuum or nonspecific solvent effects on the aminolysis reaction of N-methyl β-sultam.…”

Section: Introductionmentioning

confidence: 99%

Theoretical Studies of the Aminolysis for N‐Methyl β‐Sultam in Solution

Feng

Wang

et al. 2005

Chin. J. Chem.

View full text Add to dashboard Cite

The aminolysis and the effect of water on the aminolysis processes of n-methyl β-sultam have been studied using density functional theory (DFT) method at the B3LYP/6-31G* level. The stationary structures and energies have been investigated for both reactions to find two different reaction channels. Specific and general solvent effects have been evaluated and the most favored pathway was found. The presence of solvent disfavors the reaction, whereas the participation of water in the aminolysis reaction plays a positive role and reduces the activation energy greatly. All transition states in the assisted aminolysis are 35-70 kJ/mol lower than those for the non-assisted reaction.

show abstract

Structure–reactivity relationships in the inactivation of elastase by β-sultams

Cited by 40 publications

References 46 publications

Reactivity and selectivity in the inhibition of elastase by 3-oxo-β-sultams and in their hydrolysis

Reactivity and selectivity in the inhibition of elastase by 3-oxo-β-sultams and in their hydrolysis

A Simple and One‐Pot Synthesis of β‐Sultams by Using the Vilsmeier Reagent

Theoretical Studies of the Aminolysis for N‐Methyl β‐Sultam in Solution

Contact Info

Product

Resources

About