发现吲哚-3-丁酸衍生物作为有效的组蛋白脱乙酰酶抑制剂。

Discovery of indole-3-butyric acid derivatives as potent histone deacetylase inhibitors.

作者信息

Chen Yiming, Zhang Lihui, Zhang Lin, Jiang Qixiao, Zhang Lei

机构信息

Department of Medicinal Chemistry, School of Pharmacy, Weifang Medical University, Weifang, Shandong, China.

School of Stomatology, Weifang Medical University, Weifang, Shandong, China.

出版信息

J Enzyme Inhib Med Chem. 2021 Dec;36(1):425-436. doi: 10.1080/14756366.2020.1870457.

In discovery of HDAC inhibitors (HDACIs) with improved anticancer potency, structural modification was performed on the previous derived indole-3-butyric acid derivative. Among all the synthesised compounds, molecule exhibited high HDAC inhibitory and antiproliferative potencies in the investigations. The IC values of against HDAC1, HDAC3, and HDAC6 were 13.9, 12.1, and 7.71 nM, respectively. In the cancer cell based screening, molecule showed increased antiproliferative activities in the inhibition of U937, U266, HepG2, A2780, and PNAC-1 cells compared with SAHA. In the HepG2 xenograft model, 50 mg/kg/d of could inhibit tumour growth in athymic mice compared with 100 mg/kg/d of SAHA. Induction of apoptosis was revealed to play an important role in the anticancer potency of molecule . Collectively, a HDACI () with high anticancer activity was discovered which can be utilised as a lead compound for further HDACI design.

在发现具有更高抗癌活性的组蛋白去乙酰化酶抑制剂（HDACIs）的过程中，对先前衍生的吲哚-3-丁酸衍生物进行了结构修饰。在所有合成的化合物中，分子在研究中表现出高组蛋白去乙酰化酶抑制活性和抗增殖活性。其对HDAC1、HDAC3和HDAC6的IC 值分别为13.9、12.1和7.71 nM。在基于癌细胞的筛选中，与SAHA相比，分子在抑制U937、U266、HepG2、A2780和PNAC-1细胞方面表现出增强的抗增殖活性。在HepG2异种移植模型中，与100 mg/kg/d的SAHA相比，50 mg/kg/d的可抑制无胸腺小鼠的肿瘤生长。细胞凋亡的诱导在分子的抗癌活性中发挥重要作用。总体而言，发现了一种具有高抗癌活性的组蛋白去乙酰化酶抑制剂（），其可作为进一步设计组蛋白去乙酰化酶抑制剂的先导化合物。