Biological Evaluation and Structural Determinants of p38α Mitogen-Activated-Protein Kinase and c-Jun-N-Terminal Kinase 3 Inhibition by Flavonoids
Biological Evaluation and Structural Determinants of p38α Mitogen-Activated-Protein Kinase and c-Jun-N-Terminal Kinase 3 Inhibition by Flavonoids
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DOI：
10.1002/cbic.201000487
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发表时间：
2010-12-10
期刊：
影响因子：
3.2
通讯作者：
Laufer, Stefan
中科院分区：
文献类型：
--
作者：
Goettert, Marcia;Schattel, Verena;Laufer, Stefan
研究了42种天然黄酮类化合物和1种类黄酮葡萄糖醛酸盐对p38 α丝裂原活化蛋白激酶（p38 α）和c- jun - n末端激酶3 （JNK3）的抑制作用。发现了IC50值在低微摩尔范围内的有效抑制剂。我们评估了结构-活性关系，并将最有希望的化合物停靠在这些激酶的ATP结合位点上。在不同类别的黄酮类化合物中，黄酮醇组对p38a的抑制作用较好。其中，山奈酚-7,4'-二甲基醚是一种有效的p38 α抑制剂，对p38 α的选择性是JNK3的13倍。不含6-甲氧基的黄酮化合物优先抑制JNK3。黄酮类苷，木犀草素-7- o -糖苷，被认为是一种有效的抑制剂，对JNK3具有最大的选择性。相比之下，黄烷醇化合物对这两种激酶表现出相似的抑制活性。
A series of 42 naturally occurring flavonoids and one flavonoid glucuronide were tested for their ability to inhibit p38 alpha mitogen-activated protein kinase (p38 alpha) and c-Jun-N-terminal kinase 3 (JNK3). Potent inhibitors with IC50 values in the low micromolar range were identified. Structure-activity relationships were evaluated and the most promising compounds were docked into the ATP binding site of these kinases. Among the different classes of flavonoids, the flavonol group showed better inhibition of p38a. Of this class, kaempferol-7,4'-dimethylether was a potent p38 alpha inhibitor, displaying 13-fold selectivity for p38 alpha over JNK3. The flavone compounds without a 6-methoxy group preferentially inhibited JNK3. The flavone glycoside, luteolin-7-O-glycoside, was identified as a potent inhibitor with the greatest selectivity toward JNK3. In contrast, the flavanol compounds displayed similar inhibitory activities toward both kinases.