Acylation versus sulfonylation in the inhibition of elastase by 3-oxo-beta-sultams.
beta-Sultams are the sulfonyl analogues of beta-lactams, and 3-oxo-beta-sultams are both beta-lactams and beta-sultams and, therefore, susceptible to nucleophilic attack at either the acyl or the sulfonyl center. They are novel inactivators of serine enzymes. The second-order rate constant for the inactivation of elastase at pH 6 by N-benzyl-4,4-dimethyl-3-oxo-beta-sultam is 768 M-1 s-1, which is 103-fold greater than that with N-benzoyl beta-sultam. However, in contrast to N-acyl beta-sultams, which sulfonylate the active site serine residue to form a sulfonate ester, 3-oxo-beta-sultams inhibit the enzyme by acylation followed by slow deacylation to regenerate the active enzyme.
Tsang
Wing Y
WY
Department of Chemical and Biological Sciences, The University of Huddersfield, Huddersfield, HD1 3DH, UK.
Ahmed
Naveed
N
Harding
Lindsay P
LP
Hemming
Karl
K
Laws
Andrew P
AP
Page
Michael I
MI
D000215:Acylation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012694:Serine / Q000737:chemistry; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013450:Sulfones / Q000138:chemical synthesis*
D004791:Enzyme Inhibitors; D013449:Sulfonamides; D013450:Sulfones; D012694:Serine; D010196:Pancreatic Elastase