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KMID : 0043320120350091645
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Archives of Pharmacal Research
2012 Volume.35 No. 9 p.1645 ~ p.1654
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A novel 7-O-modified genistein derivative with acetylcholinesterase inhibitory effect, estrogenic activity and neuroprotective effect
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Shi Da Hua
Yan Zhi Qiang
Zhang Li Na
Wang Yu Rong
Jiang Chun Ping
Wu Jun Hua
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Abstract
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To find the multi-target-directed compounds for the treatment of Alzheimer’s disease (AD), we synthesized 7-(4-(diethylamino)butoxy)-5-hydroxy-3-(4-hydroxyphenyl)-4H-chromen-4-one, a novel 7-O-modified genistein derivative (GS-14), and investigated its acetylcholinesterase (AChE) inhibitory effect, estrogenic activity and neuroprotective effect. GS-14 acted as a selective AChE inhibitor in vitro, with an IC50 value of 0.17 μM and showed no inhibition activity against butyrylcholinesterase (BuChE). The Lineweaver-Burk plot revealed that GS-14 was a non-competitive AChE inhibitor with a Ki value of 0.23 μM and the molecular docking model indicated that GS-14 interacted with the peripheral anionic site (PAS) of AChE. The MCF-7 proliferation assay demonstrated that GS-14 possessed estrogenic activity and GS-14 exhibited a high specificity for estrogen receptor β (ERβ) with a dissociation constant (Ki) of 2.86 nM compared with that of 1.01 μM for estrogen receptor α (ERα) in the molecular docking study. GS-14 also possessed a neuroprotective effect and showed the best protective effect against the β-amyloid protein-induced injury on SH-SY5Y cells at a concentration of 1 nM. Considering its AChE-inhibition activity, estrogenic activity and neuroprotective effect, GS-14 may be a potential multi-target agent for the treatment of AD.
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KEYWORD
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Genistein derivative, Acetylcholinesterase (AChE) inhibitor, SH-SY5Y cell, Alzheimer’s disease (AD), Estrogenic activity, Neuroprotection
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