Osthenol, a prenylated coumarin, as a monoamine oxidase A inhibitor with high selectivity
Osthenol, a prenylated coumarin, as a monoamine oxidase A inhibitor with high selectivity
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DOI：
10.1016/j.bmcl.2019.01.016
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发表时间：
2019-03-15
影响因子：
2.7
通讯作者：
Kim, Hoon
中科院分区：
文献类型：
--
作者：
Baek, Seung Cheol;Kang, Myung-Gyun;Kim, Hoon
Osthenol（6）是一种从毛当归干燥根中分离的异戊烯化香豆素，有效地选择性抑制重组人单胺氧化酶-A（hMAO-A），IC 50值为0.74 μ M，对hMAO-A和hMAO-B显示出高选择性指数（SI > 81.1）。化合物6是可逆竞争性hMAO-A抑制剂（Ki = 0.26 μ M），其效力大于市售药物托洛沙酮（IC 50 = 0.93 μ M）。异补骨脂素（3）和巴古奇星（1），从PAPEEA CORYLIFOLIAL L.分离的呋喃香豆素衍生物，hMAO-A的IC 50值（分别为0.88和1.78 μ M）略高于6，但SI值较低（两者均为3.1）。其他受试香豆素不能有效抑制hMAO-A或hMAO-B。结构比较表明，与东莨菪碱的6-甲氧基相比，6的8-（3，3-二甲基烯丙基）基团增加了其对hMAO-A的抑制活性（4）。分子对接模拟结果表明，6与hMAO-A的结合亲和力（-8.5kcal/mol）大于hMAO-B（-5.6kcal/mol），4与hMAO-A的结合亲和力（-7.3kcal/mol）大于hMAO-B（-5.6kcal/mol）。对接模拟还表明6与hMAO-A在Phe 208处相互作用，与hMAO-B在Ile 199处通过碳氢键相互作用。我们的研究结果表明，来自天然产物的蛇床子素是一种选择性和有效的可逆的单胺氧化酶-A抑制剂，可以被视为一个潜在的先导化合物，为设计新的可逆的单胺氧化酶-A抑制剂。
Osthenol (6), a prenylated coumarin isolated from the dried roots of Angelica pubescens, potently and selectively inhibited recombinant human monoamine oxidase-A (hMAO-A) with an IC50 value of 0.74 mu M and showed a high selectivity index (SI > 81.1) for hMAO-A versus hMAO-B. Compound 6 was a reversible competitive hMAO-A inhibitor (K-i = 0.26 mu M) with a potency greater than toloxatone (IC50 = 0.93 mu M), a marketed drug. Isopsoralen (3) and bakuchicin (1), furanocoumarin derivatives isolated from Psoralea corylifolia L., showed slightly higher IC50 values (0.88 and 1.78 mu M, respectively) for hMAO-A than 6, but had low SI values (3.1 for both). Other coumarins tested did not effectively inhibit hMAO-A or hMAO-B. A structural comparison suggested that the 8-(3,3-dimethylallyl) group of 6 increased its inhibitory activity against hMAO-A compared with the 6-methoxy group of scopoletin (4). Molecular docking simulations revealed that the binding affinity of 6 for hMAO-A (-8.5 kcal/mol) was greater than that for hMAO-B (-5.6 kcal/mol) and that of 4 for hMAO-A (-7.3 kcal/mol). Docking simulations also implied that 6 interacted with hMAO-A at Phe208 and with hMAO-B at Ile199 by carbon hydrogen bondings. Our findings suggest that osthenol, derived from natural products, is a selective and potent reversible inhibitor of MAO-A, and can be regarded a potential lead compound for the design of novel reversible MAO-A inhibitors.