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Boulanger, William Allen 2014-12-15T23:18:24Z 2014-12-15T23:18:24Z 10000-01-01 1985 1985 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. Made available in DSpace on 2014-12-15T23:18:24Z (GMT). No. of bitstreams: 1 8511582.pdf: 5472943 bytes, checksum: d2678c09489e964c2b2f218f1c66caa4 (MD5) Previous issue date: 1985 Embargo set by: Seth Robbins for item 70455 Lift date: Forever Reason: Restricted to the U of I community idenfinitely during batch ingest of legacy ETDs Restricted to the U of I community idenfinitely during batch ingest of legacy ETDs U of I Only 181 p. Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1985. http://hdl.handle.net/2142/70289 (UMI)AAI8511582 Chemistry, Organic 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 text Chemistry Chemistry University of Illinois at Urbana-Champaign Dissertation Ph.D.