School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, China.
School of Biological Science and Technology, University of Jinan, Jinan 250022, China.
Molecules. 2020 Feb 7;25(3):717. doi: 10.3390/molecules25030717.
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 and 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, and , showed potent anti-proliferative activities against solid tumor cell lines with IC values of 0.36-2.91 M and low cytotoxicity against Beas-2B and L-02 normal cells. Immunoblot analysis revealed that and 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, and 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 .
组蛋白去乙酰化酶 (HDACs) 已被证实是治疗癌症的有前途的靶点，目前已有 5 种组蛋白去乙酰化酶抑制剂 (HDACis) 获批上市，用于治疗不同类型的淋巴瘤。在我们之前的工作中，我们设计了一系列新型含香豆素的羟肟酸 HDACis，其中化合物 和 对肿瘤生长表现出了有前景的活性。基于分子对接研究，我们进一步开发了 26 种额外的类似物，旨在提高设计化合物的活性。这些新衍生物中的几种不仅表现出优异的 HDAC1 抑制作用，而且对四种人癌细胞系显示出显著的生长抑制活性。代表性化合物 、 和 对实体肿瘤细胞系表现出很强的增殖抑制活性，IC 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，化合物 和 剂量依赖性地增加了组蛋白 H3 和 H4 的乙酰化。重要的是，与 SAHA 相比，这两种化合物对 MDA-MB-231 细胞系显示出更好的抗转移作用。此外，化合物 和 使 MDA-MB-231 细胞停滞在 G2/M 期，并诱导 MDA-MB-231 细胞凋亡。最后，分子对接研究合理地解释了化合物 的高活性。
