Inhibition of monoamine oxidase by (E)-styrylisatin analogues.
Inhibition of monoamine oxidase by (E)-styrylisatin analogues.
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(E)-styrylisatin 类似物抑制单胺氧化酶。
DOI：
10.1016/j.bmcl.2009.03.030
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发表时间：
2009
影响因子：
2.7
通讯作者：
Petzer,JacobusP
中科院分区：
文献类型：
--
作者：
VanderWalt,EliznaM;Milczek,ErikaM;Malan,SarelF;Edmondson,DaleE;CastagnoliJr,Neal;Bergh,JacobusJ;Petzer,JacobusP
已有研究表明，(E)-8-(3-氯苯乙烯)咖啡因(CSC)是人单胺氧化酶B(MAO-B)的特异性可逆抑制物，不与人MAO-A结合。由于小分子吲哚青素是MAO-B和MAO-A的天然可逆抑制剂，因此合成了(E)-5-苯乙酰化异硫氰酸乙酯和(E)-6-苯乙酰化异硫氰酸酯类似物，以期确定对MAO-B具有更强的效价和特异性的抑制剂。与测试的MAO制剂相比，(E)-苯乙酸乙酯类似物显示出更高的结合亲和力。(E)-5-苯乙酰胺类似物比(E)-6类似物结合更紧密，尽管后者表现出最高的MAO-B选择性。与MAO-B的分子对接研究表明，与Isatin相比，(E)-Stylisatin类似物表现出更高的结合亲和力，这最好地解释了Stylisatins连接酶的入口腔和底物腔的能力。这些类似物与人MAO-B的Ile199Ala突变体的结合较弱，证明了这一模型的实验支持。与CSC相比，MAO-A和MAO-B之间的(E)-苯乙酰胺类似物的选择性较低，这最好地解释了这两类缓蚀剂芳环的不同相对几何构型。
Previous studies have shown that (E)-8-(3-chlorostyryl)caffeine (CSC) is a specific reversible inhibitor of human monoamine oxidase B (MAO-B) and does not bind to human MAO-A. Since the small molecule isatin is a natural reversible inhibitor of both MAO-B and MAO-A, (E)-5-styrylisatin and (E)-6-styrylisatin analogues were synthesized in an attempt to identify inhibitors with enhanced potencies and specificities for MAO-B. The (E)-styrylisatin analogues were found to exhibit higher binding affinities than isatin with the MAO preparations tested. The (E)-5-styrylisatin analogues bound more tightly than the (E)-6 analogue although the latter exhibits the highest MAO-B selectivity. Molecular docking studies with MAO-B indicate that the increased binding affinity exhibited by the (E)-styrylisatin analogues, in comparison to isatin, is best explained by the ability of the styrylisatins to bridge both the entrance cavity and the substrate cavity of the enzyme. Experimental support for this model is shown by the weaker binding of the analogues to the Ile199Ala mutant of human MAO-B. The lower selectivity of the (E)-styrylisatin analogues between MAO-A and MAO-B, in contrast to CSC, is best explained by the differing relative geometries of the aromatic rings for these two classes of inhibitors.