- 作者: 林家立、賴政宇、廖韋政、廖珮馨、張淳惠
- 作者服務機構: Department of Chemistry, National Chung-Hsing University, Taichung 402, Taiwan, R.O.C.
- 中文摘要: From enzyme kinetics, 4-nitrophenyl-N-substituted carbamates 1 are characterized as pseudo-substrate inhibitors of acetylcholinesterase. However, the activity of the carbamyl enzyme does not recover in the presence of a competitive inhibitor, edrophonium. Therefore, carbamates 1 should be called as the “pseudo-pseudo-substrate” inhibitors of the enzyme. Moreover, the -logKi, logkc, and logki values are linearly correlated with Taft-Ingold equation, log (k/ko) = ρ*σ* + δ Es. A three-step AChE inhibition mechanism by carbamates 1 is proposed. The first step is the pre-equilibrium protonations of carbamates 1 with ρ* value of -1.4 from pKa-σ*-correlation. The second step is the enzyme-carbamates 1 tetrahedral intermediate formation from nucleophilic attack of the active site Ser200 on the protonated carbamates 1. Theρ* value for the -logKi-σ*-Es-correlation indicates that the true r* value for the second step is 0.5 [= -0.9 - (-1.4)]. The δ value of 0.56 for the -logKi-σ*-Es-correlation indicates that carbamates 1 with bulky substituents retarded the formation of enzyme-inhibitor tetrahedral intermediates. The third step (kc step) is the carbamylation step and is the carbamyl enzyme conjugate formation from the enzyme-carbamates 1 tetrahedral intermediate. The ρ* value of 0.21 for the logkc-correlation indicates that the transition state for the carbamylation step is more negative charge than the enzyme-carbamates 1 tetrahedral intermediate. Moreover, the kc step is insensitive to substituent effects since there is a cancellation of electronic demands for bond-making and bond-breaking components, like SN2 reactions. The δ value of 0.00 for the logkc-correlation indicates that the kc step is independent of substituent steric effect. Therefore, the product of this step carbamyl enzyme conjugate is as crowded as the enzyme-carbamates 1 tetrahedral intermediate and is likely bound to the leaving group, p-nitrophenol.
- 英文摘要: --
- 中文關鍵字: Acetylcholinesterase inhibition; LFER; QSAR; Aryl carbamates; Enzyme mechanism.
- 英文關鍵字: --