Inhibitors of BRD4 Protein from a Marine-Derived Fungus Alternaria sp. NH-F6.
Inhibitors of BRD4 Protein from a Marine-Derived Fungus Alternaria sp. NH-F6.
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DOI：
10.3390/md15030076
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发表时间：
2017-03-16
期刊：
影响因子：
5.4
通讯作者：
Ma Z
中科院分区：
文献类型：
--
作者：
Ding H;Zhang D;Zhou B;Ma Z
溴结构域（BRD）是表观遗传密码的阅读器，其通过识别乙酰赖氨酸修饰的组蛋白尾部来调节基因转录。最近，通过发现有效的抑制剂，已经证明含溴结构域蛋白如BRD 4是可药物化的。这些蛋白质-蛋白质相互作用抑制剂具有通过其深刻的抗炎和抗增殖作用来调节多种疾病的潜力。为了探索新的BRD 4抑制剂，同时为新药开发提供先导化合物，对从深海沉积物中分离的链格孢菌（Alternaria sp. NH-F6）的次级代谢产物进行了系统分析。从该菌乙酸乙酯提取物中分离得到5个新化合物，包括2个新的苝醌（1-2）、1个新的交链孢酸（3）、2-（N-乙烯基乙酰胺）-4-羟甲基-3-烯-丁内酯（4）、1个新的甘草苷（5）和19个已知化合物（6-24）。利用核磁共振（NMR）和高分辨率电喷雾电离质谱（HR-ESI-MS）分析确定了它们的结构。最后，评价了所有这些化合物对BRD 4蛋白的抑制活性，化合物2在10 μM浓度下表现出88.1%的有效抑制率。本研究提供了一种新的BRD 4抑制剂，可能具有潜在的抗肿瘤、抗病毒或抗炎药物价值。
Bromodomains (BRD) are readers of the epigenetic code that regulate gene transcription through their recognition of acetyl-lysine modified histone tails. Recently, bromodomain-containing proteins such as BRD4 have been demonstrated to be druggable through the discovery of potent inhibitors. These protein–protein interaction inhibitors have the potential to modulate multiple diseases by their profound anti-inflammatory and antiproliferative effects. In order to explore new BRD4 inhibitors as well as lead compounds for the development of new drugs, the secondary metabolites of Alternaria sp. NH-F6, a fungus isolated from deep-sea sediment samples, were analyzed systematically. Five new compounds including two new perylenequinones (1–2), one new alternaric acid (3), 2-(N-vinylacetamide)-4-hydroxymethyl-3-ene-butyrolactone (4), one new cerebroside (5), together with 19 known compounds (6–24) were isolated from the ethyl acetate extracts of this strain. Their structures were elucidated using nuclear magnetic resonance (NMR) and high resolution electrospray ionization mass spectrometry (HR-ESI-MS) analyses. Finally, all these compounds were evaluated for their inhibitory activity against BRD4 protein, and compound 2 exhibited a potent inhibition rate of 88.1% at a concentration of 10 µM. This research provides a new BRD4 inhibitor which may possess potential antitumoral, antiviral, or anti-inflammatory pharmaceutical values.