Probing structure-function relationships of serine hydrolases and proteases with carbamate and thiocarbamate inhibitors.
Benzene-1,3-di-N-n-octylcarbamate (1), benzene-1-hydroxyl-3-N-n-octylcarbamate (2), benzene-1,3-di-N-n-ocztylthiocarbamate (3), and benzene-1-hydroxyl-3-N-n-octylthiocarbamate (4) are synthesized from 1,3-benzene-diol and are characterized as the pseudo-substrate inhibitors of acetylcholinesterase, butyrylcholinesterase, cholesterol esterase, lipase, trypsin, and chymotrypsin. For these six enzyme inhibitions by 1-4, the pKi values are linearly correlated with their log ki values - Brønsted plots. Therefore, 1-4 inhibit these enzymes through a common mechanism. Moreover, both pKi and log ki values for the inhibitions by 1,3, and 4 are linearly correlated with both pKi and log ki values for the inhibitions by 2, respectively. Thus, the pKi values for the inhibitions by 2 are defined as the nucleophilicity constants of these enzymes (nenzyme). The log k2 values for the inhibitions by 1-4 are also linearly correlated with the nenzyme values. Therefore, the nucleophilicity for serine hydrolases and proteases toward 1-4 also applies the Swain-Scott correlations.
Lin
G
G
Department of Chemistry, National Chung-Hsing University, Taichung, 402, Taiwan. gilin@dragon.nchu.edu.tw
Chiou
S-Y
SY
Hwu
B-C
BC
Hsieh
C-W
CW
D000818:Animals; D002219:Carbamates; D002417:Cattle; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D004593:Electrophorus; D006736:Horses; D006867:Hydrolases / Q000737:chemistry* / Q000502:physiology; D008049:Lipase / Q000037:antagonists & inhibitors; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000502:physiology; D002787:Sterol Esterase / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013552:Swine; D013859:Thiocarbamates; D014361:Trypsin Inhibitors / Q000138:chemical synthesis
D002219:Carbamates; D002800:Cholinesterase Inhibitors; D013859:Thiocarbamates; D014361:Trypsin Inhibitors; D006867:Hydrolases; D002787:Sterol Esterase; D008049:Lipase; D012697:Serine Endopeptidases; D002918:Chymotrypsin