Synthesis and kinetic analysis of some phosphonate analogs of cyclophostin as inhibitors of human acetylcholinesterase

被引：33

作者：

Dutta, Supratik ^{[1
]}

Malla, Raj K. ^{[2
]}

Bandyopadhyay, Saibal ^{[2
]}

Spilling, Christopher D. ^{[2
]}

Dupureur, Cynthia M. ^{[1
]}

机构：

[1] Univ Missouri, Ctr Nanosci, St Louis, MO 63121 USA

[2] Univ Missouri, Dept Chem & Biochem, St Louis, MO 63121 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2010年 / 18卷 / 06期

基金：

美国国家科学基金会;

关键词：

Cyclic phosphonate; Acetylcholinesterase; Inhibitor; SELECTIVITY; DISEASE; SITE;

D O I：

10.1016/j.bmc.2010.01.063

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Two new monocyclic analogs of the natural AChE inhibitor cyclophostin and two exocyclic enol phosphates were synthesized. The potencies and mechanisms of inhibition of the bicyclic and monocyclic enol phosphonates and the exocyclic enol phosphates toward human AChE are examined. One diastereoisomer of the bicyclic phosphonate exhibits an IC50 of 3 mu M. Potency is only preserved when the cyclic enol phosphonate is intact and conjugated to an ester. Kinetic analysis indicates both a binding and a slow inactivation step for all active compounds. Mass spectrometric analysis indicates that the active site Ser is indeed phosphorylated by the bicyclic phosphonate. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：2265 / 2274

页数：10

共 22 条

[1]

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[2]

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