Synthesis and biological evaluation of lycorine derivatives as dual inhibitors of human acetylcholinesterase and butyrylcholinesterase.
Synthesis and biological evaluation of lycorine derivatives as dual inhibitors of human acetylcholinesterase and butyrylcholinesterase.
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人乙酰胆碱酯酶和丁酰胆碱酯酶双重抑制剂石蒜碱衍生物的合成及生物学评价
DOI：
10.1186/1752-153x-6-96
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发表时间：
2012-09-08
影响因子：
--
通讯作者：
Long CL
中科院分区：
文献类型：
--
作者：
Wang YH;Wan QL;Gu CD;Luo HR;Long CL
阿尔茨海默病(AD)是一种神经退行性疾病，全球有2000多万人受到影响。选择性丁酰胆碱酯酶(BChE)抑制剂和二价胆碱酯酶(CHE)抑制剂是治疗AD的新方法。合成了一系列石蒜碱衍生物(1-10)，并对其抗胆碱酯酶活性进行了评价。结果表明，新化合物2-O-tert-butyldimethylsilyl-1-O-(methylthio)methyllycorine(7)对人乙酰胆碱酯酶(HAChE)和丁酰胆碱酯酶(HBChE)具有双重抑制作用，其IC50值分别为11.40±0.66μM和4.17±0.29μM。构效关系表明：(I)石蒜碱中的1-O-(甲硫基)甲基取代基比1-O-乙酰基对胆碱酯酶有更好的抑制作用；(Ii)石蒜碱和石蒜素-2-酮的酰化或醚化衍生物对hBChE的抑制作用比HAChE更强；(Iii)石蒜碱在C-2位的氧化降低了活性。石蒜碱的酰化或醚化衍生物是hBChE和HAChE的潜在双重抑制剂。因此，进一步研究石蒜碱对胆碱酯酶抑制作用的修饰是非常必要的。
Alzheimer’s disease (AD) is a neurologically degenerative disorder that affects more than 20 million people worldwide. The selective butyrylcholinesterase (BChE) inhibitors and bivalent cholinesterase (ChE) inhibitors represent new treatments for AD. A series of lycorine derivatives (1–10) were synthesized and evaluated for anti-cholinesterase activity. Result showed that the novel compound 2-O-tert-butyldimethylsilyl-1-O-(methylthio)methyllycorine (7) was a dual inhibitor of human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) with IC50 values of 11.40 ± 0.66 μM and 4.17 ± 0.29 μM, respectively. The structure-activity relationships indicated that (i) the 1-O-(methylthio)methyl substituent in lycorine was better than the 1-O-acetyl group for the inhibition of cholinesterase; (ii) the acylated or etherified derivatives of lycorine and lycorin-2-one were more potent against hBChE than hAChE; and (iii) the oxidation of lycorine at C-2 decreases the activity. Acylated or etherified derivatives of lycorine are potential dual inhibitors of hBChE and hAChE. Hence, further study on the modification of lycorine for ChE inhibition is necessary.