Design and Synthesis of Enzyme Activated Irreversible Inactivators for Proteases. Suicide Inactivation of Chymotrypsin
Krafft, Grant Arthur
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https://hdl.handle.net/2142/67243
Description
Title
Design and Synthesis of Enzyme Activated Irreversible Inactivators for Proteases. Suicide Inactivation of Chymotrypsin
Author(s)
Krafft, Grant Arthur
Issue Date
1980
Department of Study
Chemistry
Discipline
Chemistry
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Chemistry, Organic
Language
eng
Abstract
Strategies directed toward the synthesis of halo-enol lactones have been investigated. The catalytic mercury induced lactonization of acetylenic acids has been studied, and shown to proceed via a mercuronium intermediate, to give enol lactones in good yield. This methodology was adapted to afford halo-enol lactones in modest yields, and a direct halolactonization method which gave the desired halo-enol lactones in very high yields was developed. Several other routes, such as Baeyer-Villiger oxidation of (beta)-halocycloenones and dehydration of (alpha)-haloketone acids were also developed for the synthesis of halo-enol lactones. Halo-enamine lactams were synthesized via a Schmidt reaction on (beta)-halocycloenones, and adaptation of the mercury methodology to synthesis of these compounds was also briefly explored. Initial synthetic efforts directed toward the synthesis of extended and more complex analogs also have been discussed.
Several of the halo-enol lactones inhibited (alpha)-chymotrypsin, and this inhibition was shown to be irreversible and to proceed by an enzyme mediated suicide inactivation pathway. A model has been proposed to explain the mechanism of this suicide inactivation, with regard to inactivation kinetics, pH effects and thiol reactivation results.
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