Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/70268
標題: Ortho effects and cross interaction correlations for the mechanisms of cholesterol esterase inhibition by aryl carbamates
作者: Lin, G.L.
Liu, Y.C.
Wu, Y.G.
Lee, Y.R.
關鍵字: ortho effects;cross interaction correlations;cholesterol esterase;carbamate inhibitors;structure-reactivity relationships;binding site;lipase;activation
Project: Journal of Physical Organic Chemistry
期刊/報告no:: Journal of Physical Organic Chemistry, Volume 17, Issue 8, Page(s) 707-714.
摘要: 
Ortho-substituted phenyl-N-butyl carbarnates (1-11) were synthesized to evaluate the inhibition mechanisms of porcine pancreatic cholesterol esterase. All carbarnate inhibitors act as the active site-directed pseudo substrate inhibitors of the enzymes. The logarithms of dissociation constant (K-i), carbamylation constant (k(2)) and bimolecular inhibition constant (k(i)) multiply linearly correlate with the Hammett substituent constant (sigma), the Taft-Kutter-Hansch ortho steric constant (E-S), and the Swan-Lupton-Hansch ortho polar constant (F). For the -log K-i, log k(2) and log ki correlations, the reaction constant for ordinary polar effect (rho), the intensity factor to ortho steric constant (delta) and the intensity factor to ortho polar constant (f) are 0.7, -0.07, and 0.5; 0.5, 0.04 and -0.5; and 1.1, -0.03 and 0.0, respectively. The cross interaction reaction constant (rho(XR)) for the -log k(i)-, log k(2)- and log k(i)-sigma-alphasigma*-alphasigmasigma* correlations are 3, -2, and 1, respectively. The K-i step may be composed of the following two steps: (1) protonation of carbarnates 1-11 and (2) the pseudo-trans to pseudo-cis conformation change of protonated carbamates 1-11 due to a large rho(XR) value of 3 and formation of the enzyme-protonated carbamates 1-11 tetrahedral intermediate. The k(2), step involves departure of the leaving group, which is protonated by the active site histidine of the enzyme, from the tetrahedral intermediate to solution and formation of the carbamyl enzyme. Moreover, the distances between the carbamate and phenyl groups in all transition states of inhibition reactions are relatively short owing to large \rho(XR)\ I values. The K-i step shows little ortho steric enhancement effect; moreover, the k(2) step shows little ortho steric inhibition effect. Copyright (C) 2004 John Wiley Sons, Ltd.
URI: http://hdl.handle.net/11455/70268
ISSN: 0894-3230
DOI: 10.1002/poc.740
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