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

Wing Yin Tsang, Naveed Ahmed, Karl Hemming, Michael I. Page

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

3-Oxo-β-sultams are both β-sultams and β-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-β-sultam, C-N fission, and expulsion of the sulfonamide. The lead compound, N-benzyl-4,4-dimethyl-3-oxo-β-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-β-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-β-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, ki, for inhibition whereas there is only a 100-fold difference in the second-order rate constants, kOH, 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-β-sultams by the enzyme.

Original languageEnglish
Pages (from-to)3993-4000
Number of pages8
JournalOrganic and Biomolecular Chemistry
Volume5
Issue number24
DOIs
Publication statusPublished - 30 Oct 2007

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Pancreatic Elastase
hydrolysis
Hydrolysis
reactivity
selectivity
enzymes
Enzyme inhibition
expulsion
inhibitors
Rate constants
Chemical reactivity
fission
Enzymes
enzyme inhibitors
lead compounds
acylation
Benzyl Compounds
Swine
sensitivity
Lead compounds

Cite this

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title = "Reactivity and selectivity in the inhibition of elastase by 3-oxo-β-sultams and in their hydrolysis",
abstract = "3-Oxo-β-sultams are both β-sultams and β-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-β-sultam, C-N fission, and expulsion of the sulfonamide. The lead compound, N-benzyl-4,4-dimethyl-3-oxo-β-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-β-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-β-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, ki, for inhibition whereas there is only a 100-fold difference in the second-order rate constants, kOH, 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-β-sultams by the enzyme.",
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Reactivity and selectivity in the inhibition of elastase by 3-oxo-β-sultams and in their hydrolysis. / Tsang, Wing Yin; Ahmed, Naveed; Hemming, Karl; Page, Michael I.

In: Organic and Biomolecular Chemistry, Vol. 5, No. 24, 30.10.2007, p. 3993-4000.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Reactivity and selectivity in the inhibition of elastase by 3-oxo-β-sultams and in their hydrolysis

AU - Tsang, Wing Yin

AU - Ahmed, Naveed

AU - Hemming, Karl

AU - Page, Michael I.

PY - 2007/10/30

Y1 - 2007/10/30

N2 - 3-Oxo-β-sultams are both β-sultams and β-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-β-sultam, C-N fission, and expulsion of the sulfonamide. The lead compound, N-benzyl-4,4-dimethyl-3-oxo-β-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-β-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-β-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, ki, for inhibition whereas there is only a 100-fold difference in the second-order rate constants, kOH, 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-β-sultams by the enzyme.

AB - 3-Oxo-β-sultams are both β-sultams and β-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-β-sultam, C-N fission, and expulsion of the sulfonamide. The lead compound, N-benzyl-4,4-dimethyl-3-oxo-β-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-β-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-β-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, ki, for inhibition whereas there is only a 100-fold difference in the second-order rate constants, kOH, 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-β-sultams by the enzyme.

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DO - 10.1039/b713899g

M3 - Article

VL - 5

SP - 3993

EP - 4000

JO - Organic and Biomolecular Chemistry

JF - Organic and Biomolecular Chemistry

SN - 1477-0520

IS - 24

ER -