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Title:Halo Enol Lactones as Enzyme-Activated Irreversible Inhibitors of Alpha-Chymotrypsin: I. The Effect of Lactone Substitution Pattern. Ii. Alpha - Amino-Functionalized Lactones
Author(s):Sofia, Michael Joseph
Department / Program:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Chemistry, Organic
Abstract:Halo enol lactones with a phenyl group situated (beta) or (gamma) to the lactone carbonyl group were prepared to compare their effectiveness as enzyme-activated irreversible (suicide) inhibitors for (alpha)-chymotrypsin with the activities of the corresponding (alpha)-substituted lactones. The 4-phenyl-5(E)-(iodomethylidene) tetrahydro-2-furanone, the 4-phenyl-5(E)-(iodomethylidene)dihydro-2-furanone, the 4-phenyl-6(E)-(iodomethylidene)tetrahydro-2-pyranone and the 5-phenyl-6(E)-(iodomethylidene)tetrahydro-2-pyranone were prepared using a halolactonization reaction to convert the appropriate phenyl-substituted acetylenic acid into the corresponding lactone. The 4-phenyl-tetrahydrofuranone and the 5-phenyl-tetrahydropyranone only proved to be competitive inhibitors, and the 4-phenyl-dihydrofuranone appeared to be neither an irreversible inhibitor nor a competitive inhibitor. However, the 4-phenyl-tetrahydropyranone temporarily inactivated (alpha)-chymotrypsin presumably by the formation of a stable acyl-enzyme complex as suggested by experimental data.
Also, (alpha)-amino-functionalized halo enol lactones were prepared by halolactonization of their corresponding acetylenic amino acids and investigated as suicide inhibitors of (alpha)-chymotrypsin. The 3-benzamido-5(E)-(iodomethylidene)tetrahydro-2-furanone, the 3-benzamido-3-benzyl-5(E)-(1-bromoethylidene)tetrahydro-2-furanone, the 3-acetamido-3-benzyl-5(E)-(bromomethylidene)tetrahydro-2-furanone and the 3-amino-3-benzyl-5(E)-(bromomethylidene)tetrahydro-2-furanone were shown to be only competitive inhibitors of (alpha)-chymotrypsin. A 3-benzamido-3-phenyl-5(E)-(bromomethylidene)tetrahydro-2-furanone was found to be an irreversible, but inefficient, suicide inhibitor of (alpha)-chymotrypsin.
3-Acetamido- and 3-benzamido-4-phenyl-6(E)-(iodomethylidene)tetrahydro-2-pyranones ((3R*,4R*) and (3R*,4S*)) also proved not to be suicide inhibitors of (alpha)-chymotrypsin. Experimental evidence indicates that these lactones inactivate (alpha)-chymotrypsin by a pseudosuicide mechanism or by the intermediacy of a spontaneously generated reactive species.
Issue Date:1984
Description:241 p.
Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1984.
Other Identifier(s):(UMI)AAI8502303
Date Available in IDEALS:2014-12-15
Date Deposited:1984

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