Acylation versus Sulfonylation in the Inhibition of Elastase by 3-Oxo-β-Sultams

Abstract

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.

Synthesis, conformation and antiproliferative activity of isothiazoloisoxazole 1,1-dioxides

“…The field is dominated by the β-lactams (1) [ Figure 1] due to the importance that they have acquired as anti-infective agents. [1][2][3] The corresponding β-sultams (2) are also known and have attracted attention as taurine precursors, 4,5 β-lactamase inhibitors, 6 D,D-peptidase inhibitors, 7 human neutrophil elastase inhibitors, [8][9][10] azoreductase inhibitors, 11 anti-inflammatory agents, 12 potential treatments for alcohol dependency, 13 SPase I inhibitors 14 and ClpP protease inhibitors, 15 and have attracted other mechanistic 16,17 and synthetic efforts. [18][19][20] β-Sultam chemistry been a focus of our research for some time.…”

“…[18][19][20] β-Sultam chemistry been a focus of our research for some time. [6][7][8][9][10]12,13,17 …”

[2 + 2] Annulation of Aldimines with Sulfonic Acids: A Novel One‐Pot cis‐Selective Route to β‐Sultams

“…Bacterial resistance to β‐lactam antibiotics by producing β‐lactamase and elastase is a serious concern in the fight against bacterial infections by β‐lactam antibiotics, which has motivated intensive research to overcome this problem. Recently, β‐sultams have been reported to serve as β‐lactamase‐ and elastase inhibitors by irreversible sulfonylation of the active site serine 5a,5b. The β‐sultam ring is more distorted than the β‐lactam ring, which makes β‐sultams more suitable for the design of new inhibitors.…”

Catalytic and Highly Enantioselective Reactions of α‐Sulfonyl Carbanions with Chiral Bis(oxazoline)s

“…[4] On the other hand, chiral sulfonyl analogues of carbonyl derivatives are gaining an increasingly important role in medicinal chemistry because the structural and electronic properties of the chiral sulfonyl group mimic the carbonyl moiety in the transition state, [5] and thus the catalytic asymmetric preparation of enantiomerically pure sulfonyl derivatives is in high demand. However, only a little attention has been paid to the enantioselective reactions of a-sulfonyl carbanions, which is probably due to the difficulties in obtaining high enantioselectivities for these reactions.…”

“…TMSCl was added to suppress the retroaldol-type reaction by trimethylsilylation of the formed alkoxides. Most of the reactions gave high yields of a diastereomeric mixture of the syn and anti isomers of the products 2 a-e, in which each isomer was found to have low enantioselectivity (entries [1][2][3][4][5]. On the other hand, trifluoromethyl sulfones, [10] which are known to have unusual configurational stability [11] were allowed to react at À78 8C under similar reaction conditions with a stoichiometric amount of a bis-(oxazoline) and the syn isomer (syn-2 f) was formed exclusively (entry 6).…”