ABSTRACT
Serine hydrolases are one of the largest and most diverse enzyme classes in Nature. Most serine hydrolases lack selective inhibitors, which are valuable probes for assigning functions to these enzymes. We recently discovered a set of aza-ß-lactams (ABLs) that act as potent and selective inhibitors of the mammalian serine hydrolase protein-phosphatase methylesterase-1 (PME-1). The ABLs inactivate PME-1 by covalent acylation of the enzyme's serine nucleophile, suggesting that they could offer a general scaffold for serine hydrolase inhibitor discovery. Here, we have tested this hypothesis by screening ABLs more broadly against cell and tissue proteomes by competitive activity-based protein profiling (ABPP), leading to the discovery of lead inhibitors for several serine hydrolases, including the uncharacterized enzyme α,ß-hydrolase domain-containing 10 (ABHD10). ABPP-guided medicinal chemistry yielded a compound ABL303 that potently (IC(50) ≈ 30 nM) and selectively inactivated ABHD10 in vitro and in living cells. A comparison of optimized inhibitors for PME-1 and ABHD10 indicates that modest structural changes that alter steric bulk can tailor the ABL to selectively react with distinct, distantly related serine hydrolases. Our findings, taken together, designate the ABL as a versatile reactive group for creating first-in-class serine hydrolase inhibitors.
Subject(s)
Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/pharmacology , beta-Lactams/pharmacology , Binding, Competitive/drug effects , Molecular Structure , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Stereoisomerism , Structure-Activity Relationship , beta-Lactams/chemistryABSTRACT
The appropriate choice of chiral catalyst and starting materials leads to the synthesis of 1,2-oxazetidin-3-ones by cycloadditions of ketenes with nitroso compounds with very good regioselectivity and enantioselectivity. In addition to serving as potentially bioactive target molecules, the products can be transformed into other important classes of compounds, such as alpha-hydroxycarboxylic acid derivatives.
Subject(s)
Carboxylic Acids/chemical synthesis , Ethylenes/chemistry , Ketones/chemistry , Nitroso Compounds/chemistry , Carboxylic Acids/chemistry , Catalysis , Cyclization , Heterocyclic Compounds/chemistry , StereoisomerismABSTRACT
The electronically modified zinc complex 5-phenylsulfanyl-N-isopropyl-2-(isopropylamino)troponiminate zinc methyl, [(PhS-ATI(iPr)2)ZnMe], was synthesized. It showed an increased reactivity in the intramolecular hydroamination reaction of non-activated alkenes compared to a previously-reported, non-substituted complex.
Subject(s)
Alkenes/chemistry , Amines/chemical synthesis , Imines/chemistry , Organometallic Compounds/chemistry , Tropolone/analogs & derivatives , Zinc/chemistry , Amination , Amines/chemistry , Catalysis , Crystallography, X-Ray , Electrons , Ligands , Models, Molecular , Molecular Structure , Organometallic Compounds/chemical synthesis , Stereoisomerism , Tropolone/chemistryABSTRACT
A series of symmetrical and unsymmetrical N,N'-disubstituted aminotroponimines (ATIHs) have been prepared. Substituents ranging from linear to cyclic alkyl groups, chelating ethers, and aryl groups were employed. The corresponding aminotroponiminate zinc complexes were then synthesized and characterized by a number of techniques, including by X-ray crystallography. Herein we report on the investigations into their activity in the intramolecular hydroamination of nonactivated alkenes. We also demonstrate that complexes bearing ligands with cyclic alkyl groups show superior activity in a number of selected reactions with functionalized aminoalkenes.
ABSTRACT
The new zinc compound N-cyclohexyl-2-(cyclohexylamino)troponiminate zinc methyl, [(Cy)2ATI]ZnMe, was synthesized and showed a superior reactivity in the intramolecular hydroamination reaction of non-activated alkenes compared to previously reported homogeneous zinc complexes.
