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標題: Synthesis and evaluation of a new series of tri-, di-, and mono-Nalkylcarbamylphloroglucinols as conformationally constrained inhibitors of cholesterol esterase
作者: Lin, Ming-Cheng
Lin, Gin-Zen
Hwang, Ching-In
Jian, Shuo-Yung
Lin, James
Shen, Yu-Fong
Lin, Gialih
關鍵字: cholesterol esterase;inhibitors;carbamates;molecular docking
Project: PROTEIN SCIENCE, Volume 21, page(s) 1344—1357.
1,3,5-Tri-N-alkylcarbamylphloroglucinols (1–4) are synthesized as conformationally
constrained analogs of triacylglycerols (TGs) to probe Jenck’s proximity effect in the cholesterol
esterase inhibition. For the cholesterol esterase inhibition, inhibitors 1–4 are 220–760-fold more
potent than 1,2,3-tri-N-alkylcarbamylglycerols (13–15) that are substrate analogs of TG.
Comparison of tridentate inhibitors 1–4, bidentate inhibitors 3,5-di-N-n-alkylcarbamyloxyphenols
(5–8) and monodentate inhibitors 5-N-n-alkylcarbamyloxyresorcinols (9–12) indicates that inhibitory
potencies are as followed: tridentate inhibitor > bidentate inhibitor > monodentate inhibitor. The
log ki and pKi values of tridentate inhibitors, bidentate inhibitors, and monodentate inhibitors are
linearly correlated with the alkyl chain length indicating a common mechanism in each inhibition.
Also, positive slopes of these correlations indicate that the longer chain inhibitors bind more
tightly to the enzyme than the shorter ones. Molecular dockings of tridentate 1, bidentate 5, and
monodentate 9 into the X-ray crystal structure of cholesterol esterase suggest that one carbamyl
group in the cis form of the inhibitor binds to the acyl chain-binding site of the enzyme. The
second carbamyl groups in the trans forms of inhibitors 1 and 5 bind to the second acyl chainbinding
site of the enzyme. The third carbamyl group in the trans form of inhibitor 1 binds to the
third acyl chain-binding site of the enzyme. Moreover, the configuration of the inhibitor in the
enzyme-inhibitor complex is the (1,3,5)-(cis, trans, trans)-tricarbamate form that mimics the
(1gauche, 2gauche)-conformation of TG.
DOI: 10.1002/pro.2121
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