Development of Coumarin-Based Hydroxamates as Histone Deacetylase Inhibitors with Antitumor Activities
Development of Coumarin-Based Hydroxamates as Histone Deacetylase Inhibitors with Antitumor Activities
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香豆素基异羟肟酸盐作为具有抗肿瘤活性的组蛋白脱乙酰酶抑制剂的开发
DOI：
10.3390/molecules25030717
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发表时间：
2020-02
期刊：
影响因子：
4.6
通讯作者：
Zhang Hua
中科院分区：
文献类型：
--
作者：
Zhao Na;Yang Feifei;Han Lina;Qu Yuhua;Ge Di;Zhang Hua
组蛋白去乙酰化酶（HDAC）已被证明是治疗癌症的有希望的靶点，并且五种组蛋白去乙酰化酶抑制剂（HDACis）已被批准上市用于治疗不同的淋巴瘤。在前期的工作中，我们设计了一系列新的含香豆素的异羟肟酸HDACis，其中化合物6和7显示出良好的抗肿瘤活性。基于分子对接研究，我们进一步开发了26个额外的类似物，旨在提高所设计化合物的活性。这些新的衍生物不仅表现出优异的HDAC 1抑制作用，而且还显示出对四种人癌细胞系的显著生长抑制活性。代表性化合物13 a和13 c对实体瘤细胞系显示出有效的抗增殖活性，IC 50值为0.36-2.91 μM，对Beas-2B和L-02正常细胞的细胞毒性较低。免疫印迹分析显示，13 a和13 c剂量依赖性地增加组蛋白H3和H4的乙酰化。重要的是，这两种化合物对MDA-MB-231细胞系显示出比SAHA好得多的抗转移作用。13 a和13 c可使MDA-MB-231细胞阻滞于G2/M期，并诱导MDA-MB-231细胞凋亡。最后，分子对接研究合理化了化合物13 c的高效力。
Histone deacetylases (HDACs) have been proved to be promising targets for the treatment of cancer, and five histone deacetylase inhibitors (HDACis) have been approved on the market for the treatment of different lymphomas. In our previous work, we designed a series of novel coumarin-containing hydroxamate HDACis, among which compounds 6 and 7 displayed promising activities against tumor growth. Based on a molecular docking study, we further developed 26 additional analogues with the aim to improve activity of designed compounds. Several of these new derivatives not only showed excellent HDAC1 inhibitory effects, but also displayed significant growth inhibitory activities against four human cancer cell lines. Representative compounds, 13a and 13c, showed potent anti-proliferative activities against solid tumor cell lines with IC50 values of 0.36–2.91 µM and low cytotoxicity against Beas-2B and L-02 normal cells. Immunoblot analysis revealed that 13a and 13c dose-dependently increased the acetylation of histone H3 and H4. Importantly, the two compounds displayed much better anti-metastatic effects than SAHA against the MDA-MB-231 cell line. Moreover, 13a and 13c arrested MDA-MB-231 cells at G2/M phase and induced MDA-MB-231 cell apoptosis. Finally, the molecular docking study rationalized the high potency of compound 13c.
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影响因子：
4.8
作者：
Gao, L;Cueto, MA;Atadja, P
通讯作者：
Atadja, P
影响因子：
11.5
作者：
Garnock-Jones, Karly P.
通讯作者：
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影响因子：
2.7
作者：
M. Taddei;E. Cini;L. Giannotti;G. Giannini;Gianfranco Battistuzzi;D. Vignola;L. Vesci;W. Cabri
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M. Taddei;E. Cini;L. Giannotti;G. Giannini;Gianfranco Battistuzzi;D. Vignola;L. Vesci;W. Cabri
影响因子：
4.8
作者：
Bottomley, Matthew J.;Lo Surdo, Paola;Carfi, Andrea
通讯作者：
Carfi, Andrea
影响因子：
6.7
作者：
C. Monneret
通讯作者：
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