Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hanoi, 10000, Vietnam.
College of Pharmacy, Chungbuk National University, 194-31, Osongsaengmyung-1, Heungdeok, Cheongju, Chungbuk, 28160, Republic of Korea.
Chem Biodivers. 2023 May;20(5):e202201030. doi: 10.1002/cbdv.202201030. Epub 2023 Apr 21.
Herein, we report the design, synthesis and evaluation of novel (E)-3-(3-oxo-4-substituted-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-N-hydroxypropenamides (4 a-i, 7 a-g) targeting histone deacetylases. Three human cancer cell lines were used to test the cytotoxicity of the synthesized compounds (SW620, colon; PC-3, prostate; NCI-H23, lung cancer); inhibitory activity towards HDAC; anticancer activity; as well as their impact on the cell cycle and apoptosis. As a result, compounds 4 a-i bearing the alkyl substituents seemed to be less potent than the benzyl-containing compounds 7 a-g in all biological assays. Compounds 7 e-f were found to be the most active HDAC inhibitors with IC of 1.498±0.020 μM and 1.794±0.159 μM, respectively. In terms of cytotoxicity and anticancer assay, 7 e and 7 f also showed good activity with IC values in the micromolar range. In addition, the cell cycle and apoptosis of SW620 were affected by compound 7 f in almost a similar manner to that of reference compound SAHA. Docking assays were carried out for analysis the binding mode and selectivity of this compound toward 8 HDAC isoforms. Overall, our data confirmed that the inhibition of HDAC plays a pivotal role in their anticancer activity.
在此，我们报告了新型（E）-3-（3-氧代-4-取代-3,4-二氢-2H-苯并[b][1,4]恶嗪-6-基）-N-羟丙烯酰胺（4a-i、7a-g）的设计、合成和评估，这些化合物针对组蛋白去乙酰化酶。使用三种人类癌细胞系（SW620、结肠；PC-3、前列腺；NCI-H23、肺癌）测试合成化合物的细胞毒性；对 HDAC 的抑制活性；抗癌活性；以及它们对细胞周期和细胞凋亡的影响。结果表明，带有烷基取代基的化合物 4a-i 在所有生物测定中似乎不如含有苄基的化合物 7a-g 有效。化合物 7e-f 被发现是最有效的 HDAC 抑制剂，IC 值分别为 1.498±0.020 μM 和 1.794±0.159 μM。在细胞毒性和抗癌测定方面，7e 和 7f 也表现出良好的活性，IC 值在微摩尔范围内。此外，化合物 7f 对 SW620 的细胞周期和凋亡的影响与参比化合物 SAHA 几乎相似。进行了对接实验，以分析该化合物对 8 种 HDAC 同工酶的结合模式和选择性。总的来说，我们的数据证实了 HDAC 的抑制在其抗癌活性中起着关键作用。
