β-Carboline tethered cinnamoyl 2-aminobenzamides as class I selective HDAC inhibitors: Design, synthesis, biological activities and modelling studies
β-Carboline tethered cinnamoyl 2-aminobenzamides as class I selective HDAC inhibitors: Design, synthesis, biological activities and modelling studies
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DOI：
10.1016/j.bioorg.2021.105461
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发表时间：
2021-11-06
影响因子：
5.1
通讯作者：
Kamal, Ahmed
中科院分区：
文献类型：
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作者：
Namballa, Hari Krishna;Anchi, Pratibha;Kamal, Ahmed
本研究考察了β-咔啉基序对含有肉桂酸作为接头和苯甲酰胺作为锌结合基团的HDAC抑制剂的作用。合成了一系列β-咔啉-肉桂酰胺偶联物，并评价了其HDAC抑制活性和对不同人癌细胞系的体外细胞毒性。几乎所有的化合物都表现出上级标准药物恩替司他的体外酶促测定的HDAC抑制活性。在测试的化合物中，当与标准药物恩替诺司他（3.87 +/-0.62 μ M的IC 50）相比时，7 h显示出显著的效力，其针对HCT-15细胞系的IC 50值为0.70 +/-0.15 μ M。传统的细胞凋亡检测如细胞核形态学改变、AO/EB、DAPI和Annexin-V/PI染色显示JC-1在7 h具有抗增殖活性，同时观察到JC-1以剂量依赖性方式使线粒体膜电位去极化。细胞周期分析也显示了典型的G（2）M期细胞聚集和亚G（1）/5期阻滞。此外，化合物7 h在HCT-15上的免疫印迹分析表明选择性抑制I类HDAC 2和3同种型的蛋白质表达。对化合物7 h的分子对接分析表明，它可以与HDAC 2的活性口袋显著结合。这些发现表明，化合物7 h可能是一个有前途的主要候选人，用于进一步研究开发新的抗癌药物，可能抑制HDAC。
The effect of beta-carboline motif as cap for HDAC inhibitors containing cinnamic acid as linker and benzamides as zinc binding group was examined in this study. A series of beta-carboline-cinnamide conjugates have been synthesized and evaluated for their HDAC inhibitory activity and in vitro cytotoxicity against different human cancer cell lines. Almost all the compounds exhibited superior HDAC inhibitory activity than the standard drug Entinostat for in vitro enzymatic assay. Among the tested compounds, 7h displayed a noteworthy potency with an IC50 value of 0.70 +/- 0.15 mu M against HCT-15 cell line when compared to the standard drug Entinostat (IC50 of 3.87 +/- 0.62 mu M). The traditional apoptosis assays such as nuclear morphological alterations, AO/EB, DAPI, and Annexin-V/PI staining revealed the antiproliferative activity of 7h while depolarization of mitochondrial membrane potential by JC-1 was observed in dose-dependent manner. Cell cycle analysis also unveiled the typical accumulation of cells in G(2)M phase and sub-G(1)/5 phase arrest. In addition, immunoblot analysis for compound 7h on HCT-15 indicated selective inhibition of the protein expression of class I HDAC 2 and 3 isoforms. Molecular docking analysis of compound 7h revealed that it can prominent binding with the active pocket of the HDAC 2. These finding suggest that the compound 7h can be a promising lead candidate for further investigation in the development of novel anti-cancer drug potentially inhibiting HDACs.