磺胺查尔酮对β-分泌酶和乙酰胆碱酯酶的抑制评价。
Inhibitory evaluation of sulfonamide chalcones on β-secretase and acylcholinesterase.
机构信息
Division of Applied Life Science (BK21 Program), IALS, Gyeongsang National University, Jinju, Korea.
出版信息
Molecules. 2012 Dec 21;18(1):140-53. doi: 10.3390/molecules18010140.
The action of β-secretase (BACE1) is strongly correlated with the onset of Alzheimer's disease (AD). Aminochalcone derivatives were examined for their ability to inhibit BACE1. Parent aminochalcones showed two digit micromolar IC(50)s against BACE1. Potency was enhanced 10-fold or more by introducing benzenesulfonyl derivatives to the amino group: 1 (IC(50) = 48.2 μM) versus 4a (IC(50) = 1.44 μM) and 2 (IC(50) = 17.7 μM) versus 5a (IC(50) = 0.21 μM). The activity was significantly influenced by position and number of hydroxyl groups on the chalcone B-ring: 3,4-dihydroxy 5a (IC(50) = 0.21 μM) > 4-hydroxy 4a (IC(50) = 1.44 μM) > 2,4-dihydroxy 6 (IC(50) = 3.60 μM) > 2,5-dihydroxy 7 (IC(50) = 16.87 μM) > des hydroxy 4b (IC(50) = 168.7 μM). Lineweaver-Burk and Dixon plots and their secondary replots indicate that compound 5a was a mixed inhibitor with reversible and time-dependent behavior. Potent BACE1 inhibitors 4a,c,f, 5a-c showed moderate inhibition against two other enzymes implicated in AD pathogenesis, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with IC(50)s ranging between 56.1 ~ 95.8 μM and 19.5 ~ 79.0 μM, respectively.
β-分泌酶（BACE1）的活性与阿尔茨海默病（AD）的发病密切相关。本研究考察了氨基查耳酮衍生物抑制 BACE1 的能力。母本氨基查耳酮对 BACE1 的抑制活性为两个数量级的微摩尔级，即 1（IC50=48.2 μM）和 2（IC50=17.7 μM）。将苯磺酰基衍生物引入氨基后，活性提高了 10 倍以上：4a（IC50=1.44 μM）和 5a（IC50=0.21 μM）。查耳酮 B 环上羟基的位置和数量对活性有显著影响：3,4-二羟基 5a（IC50=0.21 μM）>4-羟基 4a（IC50=1.44 μM）>2,4-二羟基 6（IC50=3.60 μM）>2,5-二羟基 7（IC50=16.87 μM）>去羟基 4b（IC50=168.7 μM）。Lineweaver-Burk 和 Dixon 作图及其二级 replot 表明，化合物 5a 是一种具有可逆和时间依赖性的混合抑制剂。具有强 BACE1 抑制活性的化合物 4a,c,f,5a-c 对另外两种与 AD 发病机制相关的酶，乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）也有中等抑制作用，IC50 分别为 56.195.8 μM 和 19.579.0 μM。
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