Design, synthesis and anti-Alzheimer's disease activity study of xanthone derivatives based on multi-target strategy

被引：47

作者：

Kou, Xiaodi ^{[1
]}

Song, Lulu ^{[1
]}

Wang, Yunhua ^{[2
]}

Yu, Qiao ^{[1
]}

Ju, Hui ^{[1
]}

Yang, Aihong ^{[1
]}

Shen, Rui ^{[1
]}

机构：

[1] Tianjin Univ Tradit Chinese Med, Coll Tradit Chinese Med, Tianjin 301617, Peoples R China

[2] Tianjin Univ Tradit Chinese Med, Coll Hlth Sci & Engn, Tianjin 301617, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2020年 / 30卷 / 04期

基金：

中国国家自然科学基金;

关键词：

Alzheimer's disease; Xanthone derivatives; Acetylcholinesterase inhibitor; Multi-target strategy; CHOLINESTERASE-INHIBITORS; BIOLOGICAL EVALUATION; DIRECTED LIGANDS; OXIDATIVE STRESS; AGENTS;

D O I：

10.1016/j.bmcl.2019.126927

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of xanthone derivatives were designed, synthesized and evaluated as multifunctional ligands against Alzheimer's disease (AD). In vitro studies showed all xanthone derivatives had good metal chelating property and exhibited selective inhibitory activity against Acetylcholinesterase (AChE). In particular, compound 2a showed the highest inhibitory activity against AChE, and the IC50 value was (0.328 +/- 0.001) mu M, which was comparable to tacrine. Kinetic analysis and molecular docking studies indicated that these derivatives targeted both the catalytically active site (CAS) and the peripheral anion site (PAS) of AChE. Moreover, all derivatives showed higher anti-oxidative activity than vitamin C. Furthermore, copper complex had higher anti-AChE activity and antioxidant activity. Thus, these xanthone derivatives are potential multi-targeted-directed ligands for further development for the treatment of AD.

引用

页数：5

共 29 条

[1] Multi-Target-Directed Ligands and other Therapeutic Strategies in the Search of a Real Solution for Alzheimer's Disease [J].

Agis-Torres, Angel ;

Soellhuber, Monica ;

Fernandez, Maria ;

Sanchez-Montero, J. M. .

CURRENT NEUROPHARMACOLOGY, 2014, 12 (01) :2-36

[2] 2018 Alzheimer's disease facts and figures [J].

不详 .

ALZHEIMERS & DEMENTIA, 2018, 14 (03) :367-425

[3] Alzheimer's disease [J].

Scheltens, Philip ;

De Strooper, Bart ;

Kivipelto, Miia ;

Holstege, Henne ;

Chetelat, Gael ;

Teunissen, Charlotte E. ;

Cummings, Jeffrey ;

van der Flier, Wiesje M. .

LANCET, 2021, 397 (10284) :1577-1590

[4] The Catalytically Active Copper-Amyloid-Beta State: Coordination Site Responsible for Reactive Oxygen Species Production [J].

Cassagnes, Laure-Estelle ;

Herve, Vincent ;

Nepveu, Francoise ;

Hureau, Christelle ;

Faller, Peter ;

Collin, Fabrice .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2013, 52 (42) :11110-11113

[5] A NEW AND RAPID COLORIMETRIC DETERMINATION OF ACETYLCHOLINESTERASE ACTIVITY [J].

ELLMAN, GL ;

COURTNEY, KD ;

ANDRES, V ;

FEATHERSTONE, RM .

BIOCHEMICAL PHARMACOLOGY, 1961, 7 (02) :88-&

[6] Identification and evaluation of apoptotic compounds from Garcinia oligantha [J].

Gao, Xue-Mei ;

Yu, Ting ;

Cui, Ming-zhu ;

Pu, Jian-Xin ;

Du, Xue ;

Han, Quan-bin ;

Hu, Qiu-fen ;

Liu, Tian-Cheng ;

Luo, Kathy Qian ;

Xu, Hong-Xi .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2012, 22 (06) :2350-2353

[7] Oxidative stress in Alzheimer disease [J].

Gella, Alejandro ;

Durany, Nuria .

CELL ADHESION & MIGRATION, 2009, 3 (01) :88-93

[8] Homeostasis of metals in the progression of Alzheimer's disease [J].

Gonzalez-Dominguez, Raul ;

Garcia-Barrera, Tamara ;

Luis Gomez-Ariza, Jose .

BIOMETALS, 2014, 27 (03) :539-549

[9] SUPEROXIDE-DEPENDENT FORMATION OF HYDROXYL RADICALS IN PRESENCE OF IRON CHELATES - IS IT A MECHANISM FOR HYDROXYL RADICAL PRODUCTION IN BIOCHEMICAL SYSTEMS [J].

HALLIWELL, B .

FEBS LETTERS, 1978, 92 (02) :321-326

[10] Redox-active metals, oxidative stress, and Alzheimer's disease pathology [J].

Huang, XD ;

Moir, RD ;

Tanzi, RE ;

Bush, AI ;

Rogers, JT .

REDOX-ACTIVE METALS IN NEUROLOGICAL DISORDERS, 2004, 1012 :153-163

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