A novel 7-O-modified genistein derivative with acetylcholinesterase inhibitory effect, estrogenic activity and neuroprotective effect.
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 K(i) 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 (K(i)) 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.
Institute of Functional Biomolecules, Jiangsu Key Laboratory of Molecular Medicine, State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing, 210093, China.
Da-Hua
DH
Shi
Zhi-Qiang
ZQ
Yan
Li-Na
LN
Zhang
Yu-Rong
YR
Wang
Chun-Ping
CP
Jiang
Jun-Hua
JH
Wu
D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000737:chemistry / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists / Q000737:chemistry / Q000378:metabolism; D004968:Estrogens, Non-Steroidal / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019833:Genistein / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D061986:MCF-7 Cells; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018697:Nootropic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding
C578980:7-(4-(diethylamino)butoxy)-5-hydroxy-3-(4-hydroxyphenyl)-4H-chromen-4-one; D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004968:Estrogens, Non-Steroidal; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D019833:Genistein; D000110:Acetylcholinesterase