2-Pyranones as Suicide Inhibitors for Alpha-Chymotrypsin: I. A Structure-Activity Study of the 6-Halo-2-Pyranones. Ii. 5-Halomethyl-2-Pyranones as Inhibitors of Chymotrypsin
Boulanger, William Allen
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https://hdl.handle.net/2142/70289
Description
Title
2-Pyranones as Suicide Inhibitors for Alpha-Chymotrypsin: I. A Structure-Activity Study of the 6-Halo-2-Pyranones. Ii. 5-Halomethyl-2-Pyranones as Inhibitors of Chymotrypsin
Author(s)
Boulanger, William Allen
Issue Date
1985
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
A structure-activity study was done on a series of 6-halo-2-pyranones as suicide inhibitors of chymotrypsin. In the 6-chloro-2-pyranone series, substitution in the 3- position of the pyrone by either ethyl or n-butyl produced poor binding relative to 3-benzyl-6-chloro-2-pyranone, and no inactivation. Increasing the aromatic area of the binding group by replacing the benzyl group with a naphthylmethyl had a dramatically different effect, depending upon the naphthyl substitution; 3-(2-naphthyl)methyl-6-chloro-2-pyranone inhibited chymotrypsin 33-fold faster than the benzyl pyrone and 100-fold faster than the 1-naphthyl isomer. Models suggest that this great difference is a consequence of binding, not steric inhibition.
By removing the methylene of the benzyl pyrone to give 3-phenyl-6-chloro-2-pyranone, no irreversible inhibition was observed, though the compound proved to be a remarkably good competitive inhibitor (K(,i) = 0.27 uM). Computer models suggest that it may be a substrate sterically unable to ring-open. In contrast, 4-phenyl-6-chloro-2-pyranone is a very rapid inactivator of chymotrypsin, but the also rapid reactivation suggests that it mimics ethyl cinnamate and simply acylates serine.
6-Chloropyrones are faster inactivators than 6-bromopyrones; 6-proteopyrones bind more poorly than the 6-halopyrones, are not substrates, and do not inactivate chymotrypsin, indicating the need for ring-activation if this system is to be used as the basis of suicide inhibitors. Electron withdrawing, non-leaving groups such as 5- or 6-trifluoromethyl do not activate the pyrone in lieu of halogen.
Two kinds of 5-halomethyl-2-pyranones were surveyed as possible suicide inhibitors for chymotrypsin; 5-chloromethyl-2-pyranones and 5-trifluoromethyl-2-pyranones. Neither type proved to be a substrate, though the 5-chloromethyl pyrones inactivated chymotrypsin with great efficiency (1.38 to 2.0 equivalents), apparently by an affinity-labelling mechanism.
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