Discovery of 1,2,4-oxadiazole-Containing hydroxamic acid derivatives as histone deacetylase inhibitors potential application in cancer therapy
Discovery of 1,2,4-oxadiazole-Containing hydroxamic acid derivatives as histone deacetylase inhibitors potential application in cancer therapy
复制标题
发现含有 1,2,4-恶二唑的异羟肟酸衍生物作为组蛋白脱乙酰酶抑制剂在癌症治疗中的潜在应用
DOI：
10.1016/j.ejmech.2019.05.089
复制
发表时间：
2019
影响因子：
6.7
通讯作者：
Chen Lijuan
中科院分区：
文献类型：
--
作者：
Yang Zhuang;Shen Mingsheng;Tang Minghai;Zhang Wanhua;Cui Xue;Zhang Zihao;Pei Heying;Li Yong;Hu Mengshi;Bai Peng;Chen Lijuan
In this study, a series of novel HDAC inhibitors, using 1,2,4-oxadiazole-containing as the cap group, were synthesized and evaluated in vitro. Compound14b,N-hydroxy-2-(methyl((3-(1-(4-methylbenzyl)piperidin-4-yl)-1,2,4-oxadiazol-5-yl)methyl)amino)pyrimidine-5-carboxamide, displayed the most potent histone deacetylase (HDAC) inhibition, especially against HDAC1, 2, and 3 with IC50values of 1.8, 3.6 and 3.0 nM, respectively. In vitro antiproliferative studies confirmed that14bwas more potent than SAHA, with IC50values against 12 types of cancer cell lines ranging from 9.8 to 44.9 nM. The results of Western blot assays showed that compound14bcan significantly up-regulate the acetylation of the biomarker his-H3and molecular docking analyses revealed the mode of action of compound14bagainst HDAC1. The results of flow-cytometry analysis suggested that compound14binduces cell cycle arrest at the G1 phase and has apoptotic effects. Further investigation of the activity of14bon the primary cells of three patients, showed IC50values of 21.3, 61.1, and 77.4 nM. More importantly, an oral bioavailability of up to 53.52% was observed for14b. An in vivo pharmacodynamic evaluation demonstrated that compound14bcan significantly inhibit tumor growth in a Daudi Burkitt's lymphoma xenograft model, with tumor inhibition rates of 53.8 and 46.1% observed at 20 and 10 mg/kg when administered p.o. and i.v., respectively. These results indicate that compound14bmay be a suitable lead for further evaluation and development as an HDAC inhibitor and a potent anticancer agent.
