1-Acylamido boronic acids and Difluoroborane analogs of amino acids: Synthesis and biological activity of transition state analogs for Chymotrypsin and Elastase (inhibition, esters)
Kinder, David Harold
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https://hdl.handle.net/2142/70252
Description
Title
1-Acylamido boronic acids and Difluoroborane analogs of amino acids: Synthesis and biological activity of transition state analogs for Chymotrypsin and Elastase (inhibition, esters)
Author(s)
Kinder, David Harold
Issue Date
1984
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
Abstract
"Several acylamido boronic acids and difluoroborane analogs of amino acids, some as single enantiomers, have been synthesized and evaluated as ""transition state"" inhibitors of the serine proteases (alpha)-chymotrypsin and elastase. These inhibitors were designed to resemble N-acyl phenylalanine, phenylglycine (as chymotrypsin inhibitors), alanine, valine, and isoleucine (as elastase inhibitors) and have boron sybstituted for the carboxy terminus carbon. Acyl groups were benzoyl, benzyloxycarbonyl-alanyl (Z-alanyl) and Z-glycinyl."
These inhibitors were synthesized by displacing chloride adjacent to boron of 1-chloroboronic esters with the protected amid base lithium hexamethyldisilylamide, to generate the 1-(bis-(trimethylsilyl)amino)-boronic esters. These esters were, in turn, acylated under neutral conditions with acyl carbonates or acyl phosphonates with concomitant fluoride ion or water deprotection. The putative acylating agents were formed from the cesium salt of the acid or amino acid and a corresponding chloroformate or chlorophosphonate.
The R enantiomers of these analogs were synthesized from (+)-pinanediol boronic esters where the pinanediol induces a preference for the S 1-chloroboronates during a homologation reaction of the boronic ester with dichloromethyllithium. Subsequent displacement of chloride with lithium hexamethyldisilylamide results in the R 1-amino boronates (the R configuration corresponds to the L amino acids).
The difluoroborane analogs were more easily purified than the boronic acids. However, they appear to be completely hydrolyzed in aqueous buffer, and are thus biologically equivalent to the boronic acids.
These analogs were potent inhibitors of chymotrypsin and elastase, with K(,i)'s ranging from 0.3-8.0 and 0.1-35 (mu)M, respectively. These inhibitors were compared to analogous substrates, and the chymotrypsin inhibitors were found to behave as true transition state analogs. The elastase inhibitors could not be shown to be true transition state inhibitors based on the substrates available for comparison.
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