Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/35194
標題: Synthesis and Evaluation of a New Series of Tri-, Di-, and Mono-N-alkylcarbamylphloroglucinols as Bulky Inhibitors of Acetylcholinesterase
作者: Lin, Ming-Chen
Lin, Gin-Zen
Shen, Yu-Fong
Jian, Shuo-Yung
Hsieh, Dean-Kuo
Lin, James
Lin, Gialih
Project: Chemical Research in Toxicology, Volume 25 , Issue 7, page(s) 1462–1471.
摘要: 
1,3,5-Tri-N-alkylcarbamylphloroglucinols (1−4) are synthesized
as a new series of bulky inhibitors of acetylcholinesterase that may block
the catalytic triad, the anionic substrate binding site, and the entrance of the
enzyme simultaneously. Among three series of phloroglucinol-derived
carbamates, tridentate inhibitors 1,3,5-tri-N-alkylcarbamylphloroglucinols
(1−4), bidentate inhibitors 3,5-di-N-n-alkylcarbamyloxyphenols (5−8), and
monodentate inhibitors 5-N-n-alkylcarbamyloxyresorcinols (9−12), tridentate
inhibitors 1−4 are the most potent inhibitors of mouse acetylcholinesterase.
When different n-alkylcarbamyl substituents in tridentate inhibitors 1−4 are
compared, n-octylcarbamate 1 is the most potent inhibitor of the enzyme. All
inhibitors 1−12 are characterized as the pseudo substrate inhibitors of
acetylcholinesterase. Thus, tridentate inhibitors 1−4 are supposed to be
hydrolyzed to bidentate inhibitors 5−8 after the enzyme catalysis. Subsequently,
bidentate inhibitors 5−8 and monodentate inhibitors 9−12 are supposed to yield monodentate inhibitors 9−12 and phloroglucinol,
respectively, after the enzyme catalysis. This means that tridentate inhibitors 1−4 may act as long period inhibitors of the enzyme.
Therefore, inhibitors 1−4 may be considered as a new methodology to develop the long-acting drug for Alzheimer's disease.
Automated dockings of inhibitor 1 into the X-ray crystal structure of acetylcholinesterase suggest that the most suitable configuration
of inhibitor 1 to the enzyme binding is the (1,3,5)- (cis,trans,trans)-tricarbamate rotamer. The cis-carbamyl moiety of this rotamer
does not bind into the acetyl group binding site of the enzyme but stretches out itself to the entrance. The other two trans-carbmayl
moieties of this rotamer bulkily block the tryptophan 86 residue of the enzyme.
URI: http://hdl.handle.net/11455/35194
DOI: 10.1021/tx300119a
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