5-(Halomethyl)-2-pyranones as irreversible inhibitors of alpha-chymotrypsin.
A series of 5-(halomethyl)-2-pyranones were prepared and assayed as potential mechanism-based inhibitors of chymotrypsin, in order to test whether substitution of a suitable electron-withdrawing group at position 5 in a 2-pyranone can activate the ring for catalytic hydrolysis, as well as form a mechanism-based inhibitor. 3-Benzyl-5-(chloromethyl)-2-pyranone (3) and 3-(1-naphthylmethyl)-5-(chloromethyl)-2-pyranone (4) rapidly and irreversibly inactivate chymotrypsin with high efficiency (I/E = 2.0 for 3 and 1.38 for 4). However, evidence for their formation of an acyl enzyme is lacking, and thus they may simply be active-site alkylating agents. 6-Methyl substitution on 4, or replacement of the chloromethyl of 3 with CF3, prevents inactivation. Since 6-bromo substitution is capable of ring activation, but 5-bromo substitution (3-benzyl-5-bromo-2-pyranone (11)) is not, the 5-position of the pyrone does not appear to affect catalytic hydrolysis.
D000478:Alkylation; D002918:Chymotrypsin / Q000037:antagonists & inhibitors*; D006207:Half-Life; D008623:Mercaptoethanol / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011714:Pyrans / Q000138:chemical synthesis*; D011753:Pyrones / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013997:Time Factors
D011480:Protease Inhibitors; D011714:Pyrans; D011753:Pyrones; D008623:Mercaptoethanol; D002918:Chymotrypsin