Natural chalcones as dual inhibitors of HDACs and NF-κB.
Natural chalcones as dual inhibitors of HDACs and NF-κB.
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DOI：
10.3892/or.2012.1870
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发表时间：
2012-09
期刊：
影响因子：
4.2
通讯作者：
Tasdemir D
中科院分区：
文献类型：
--
作者：
Orlikova B;Schnekenburger M;Zloh M;Golais F;Diederich M;Tasdemir D
组蛋白脱乙酰酶（HDAC）正在成为癌症和炎症的有希望的生物靶标。使用荧光测定法，我们测试了21种天然查耳酮的体外HDAC抑制活性，查耳酮是一组广泛存在的具有众所周知的抗炎和抗肿瘤作用的天然产物。由于HDAC调节转录因子NF-κB的表达，我们还评估了化合物对NF-κB活化的抑制潜力。只有四种查耳酮，异甘草素（编号10），紫铆（编号12），高紫铆（编号15）和苷marein（编号21）显示HDAC抑制活性，IC 50值为60-190 μM，而许多化合物抑制TNFα诱导的NF-κB活化，IC 50值在8-41 μM范围内。有趣的是，三个查耳酮（nos. 10、12和15）抑制TNFα诱导的NF-κB活性和I、II和IV类总HDAC活性。分子模拟和对接研究揭示了双重活性和绘制查尔酮（NOS）之间的结构-活性关系。第1-21段）。据我们所知，这是第一项为HDAC作为天然查尔酮潜在药物靶点提供证据的研究。首次研究了所选查尔酮对NF-κB和HDAC的双重抑制潜力。这项研究表明，查耳酮可以作为开发双重抑制剂的先导化合物，用于治疗炎症和癌症。
Histone deacetylase enzymes (HDACs) are emerging as a promising biological target for cancer and inflammation. Using a fluorescence assay, we tested the in vitro HDAC inhibitory activity of twenty-one natural chalcones, a widespread group of natural products with well-known anti-inflammatory and antitumor effects. Since HDACs regulate the expression of the transcription factor NF-κB, we also evaluated the inhibitory potential of the compounds on NF-κB activation. Only four chalcones, isoliquiritigenin (no. 10), butein (no. 12), homobutein (no. 15) and the glycoside marein (no. 21) showed HDAC inhibitory activity with IC50 values of 60–190 μM, whereas a number of compounds inhibited TNFα-induced NF-κB activation with IC50 values in the range of 8–41 μM. Interestingly, three chalcones (nos. 10, 12 and 15) inhibited both TNFα-induced NF-κB activity and total HDAC activity of classes I, II and IV. Molecular modeling and docking studies were performed to shed light into dual activity and to draw structure-activity relationships among chalcones (nos. 1–21). To the best of our knowledge this is the first study that provides evidence for HDACs as potential drug targets for natural chalcones. The dual inhibitory potential of the selected chalcones on NF-κB and HDACs was investigated for the first time. This study demonstrates that chalcones can serve as lead compounds in the development of dual inhibitors against both targets in the treatment of inflammation and cancer.
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