The synthesis and evaluation of halo and protio enol lactone Pro-Val pseudodipeptides as potential inhibitors of human leukocyte elastase
Reed, Peter E.
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https://hdl.handle.net/2142/22109
Description
Title
The synthesis and evaluation of halo and protio enol lactone Pro-Val pseudodipeptides as potential inhibitors of human leukocyte elastase
Author(s)
Reed, Peter E.
Issue Date
1990
Doctoral Committee Chair(s)
Katzenellenbogen, John A.
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, Biochemistry
Chemistry, Organic
Chemistry, Pharmaceutical
Language
eng
Abstract
Mechanism-based inhibitors of the serine protease $\alpha$-chymotrypsin have previously been prepared from aryl-substituted halo and protio enol lactones. In this study, the enantiomerically pure disubstituted protio and halo enol lactones 11a-c and 12a-b were prepared as potential inhibitors of the serine protease human leukocyte elastase (HLE). These lactones are incorporated into a Pro-Val pseudodipeptide in order to enhance binding and specificity towards HLE. The synthesis of these compounds proceeded by the cyclization of N-protected forms of the acetylenic amino acid epimers 13a and 13b. The amino acids were obtained by amide bond hydrolysis of the bicyclic oxa lactams 19a and 19b, prepared in six steps from Boc-(L)-proline.
One of the target lactones, the trans bromo enol lactone 12a, is a potent inhibitor of HLE and $\alpha$-chymotrypsin, but a much poorer inhibitor of serine proteases of different specificity. Inactivation rates (k$\sb{\rm obs}$/I$\sb{\rm o}$), binding constants (K$\sb{\rm I}$), acylation rates (k$\sb{\rm a}$), and turnover numbers (TON) have been determined for the inhibition of HLE and $\alpha$-chymotrypsin by the lactone 12a, and the results are consistent with a mechanism-based inhibition process. Slow, partial reactivation of HLE was noted when the nucleophile hydrazine was added to a solution of the inactivated enzyme. A proposed mechanism for HLE inhibition involves the partitioning of the initially formed acyl enzyme intermediate into three species.
In an unrelated study, the stability of the $\beta$-substituted $\beta$-phenylpropionyl chymotrypsin 48 derived from the protio enol lactone alternate substrate inhibitor 46 was investigated by preparing a series of $\beta$-substituted $\beta$-phenylpropionyl chymotrypsins possessing nonpolar, polar, and acylamino $\beta$-substituents. The results indicate that the $\beta$-substituent contributes to acyl enzyme stability by both steric and electronic interactions with the enzyme. An acyl enzyme structure that is twisted out of an orientation optimal for deacylation is proposed.
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