100129-60-0Relevant academic research and scientific papers
Ortho effects and cross interaction correlations for the mechanisms of cholesterol esterase inhibition by aryl carbamates
Lin, Gialih,Liu, Yu-Chen,Wu, Yon-Gi,Lee, Yu-Ru
, p. 707 - 714 (2004)
Ortho-substituted phenyl-N-butyl carbamates (1-11) were synthesized to evaluate the inhibition mechanisms of porcine pancreatic cholesterol esterase. All carbamate inhibitors act as the active site-directed pseudo substrate inhibitors of the enzymes. The logarithms of dissociation constant (K i), carbamylation constant (k2) and bimolecular inhibition constant (ki) multiply linearly correlate with the Hammett substituent constant (σ), the Taft-Kutter-Hansch ortho steric constant (Es), and the Swan-Lupton-Hansch ortho polar constant (F). For the -log Ki, log k2 and log ki correlations, the reaction constant for ordinary polar effect (ρ), the intensity factor to ortho steric constant (δ) 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 (ρXR) for the -log ki-, log k2- and log ki-σ- ασ*-ασσ* correlations are 3, -2, and 1, respectively. The Ki step may be composed of the following two steps: (1) protonation of carbamates 1-11 and (2) the pseudo-trans to pseudo-cis conformation change of protonated carbamates 1-11 due to a large ρXR value of 3 and formation of the enzyme-protonated carbamates 1-11 tetrahedral intermediate. The k2 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 |ρXR| values. The Ki step shows little ortho steric enhancement effect; moreover, the k2 step shows little ortho steric inhibition effect. Copyright
