有机化学 ›› 2019, Vol. 39 ›› Issue (7): 1983-1989.DOI: 10.6023/cjoc201812036 上一篇    下一篇

研究论文

西达本胺衍生物的设计合成及抗肿瘤活性评价

张祥娜, 何峰, 张秋琼, 吕佳徽, 徐阿娜, 虞成功, 曲颖, 吴敬德   

  1. 山东大学药学院化学生物学教育部重点实验室 济南 250012
  • 收稿日期:2018-12-19 修回日期:2019-01-12 出版日期:2019-07-25 发布日期:2019-03-29
  • 通讯作者: 吴敬德 E-mail:wujingde70@sdu.edu.cn
  • 基金资助:

    山东省重点研发计划(No.2017CXGC1401)资助项目.

Design, Synthesis and Evaluation of Anti-tumor Activities of Chidamide Derivatives

Zhang Xiangna, He Feng, Zhang Qiuqiong, Lü Jiahui, Xu A'na, Yu Chenggong, Qu Ying, Wu Jingde   

  1. Key Laboratory of Chemical Biology(Ministry of Education), School of Pharmaceutical Science, Shandong University, Jinan 250012
  • Received:2018-12-19 Revised:2019-01-12 Online:2019-07-25 Published:2019-03-29
  • Contact: 10.6023/cjoc201812036 E-mail:wujingde70@sdu.edu.cn
  • Supported by:

    Project supported by the Key Research and Development Plan of Shandong Province (No. 2017CXGC1401).

以西达本胺为基础设计合成了一系列新型组蛋白去乙酰化酶(HDACs)抑制剂,以提高与Zn2+的螯合作用和亚型选择性.大部分化合物表现出一定的抗肿瘤增殖活性.其中,(E)-N-(4-氨基-6-氟-[1,1'联苯]3-基)-4-((3-(吡啶-3-基)丙烯酰氨基)甲基)苯甲酰胺(7i)和(E)-N-(2-氨基-4-氟-5-(噻吩-2-基)苯基)-4-((3-(吡啶-3-基)丙烯酰胺基)甲基)苯甲酰胺(7j)抗肿瘤增殖活性最佳,对Jurkat细胞的IC50分别为3.29和12.59 μmol/L,并且这两个化合物表现出一定的HDAC抑制活性,为更有潜力的西达本胺衍生物的设计合成提供了新思路.

关键词: 西达本胺, HDACs, 抗肿瘤活性, 苯甲酰胺

A series of novel chidamide based histone deacetylases (HDACs) inhibitors were rationally designed and synthesized to increase the Zn2+ chelating and selectivity. Biological characterization established that most of the compounds showed moderate antiproliferative activitites in cancer cell lines. Among the tested analogs, (E)-N-(4-amino-6- fluoro-[1,1'-biphenyl]-3-yl)-4-((3-(pyridin-3-yl)acrylamido)methyl)benzamide (7i) and (E)-N-(2-amino-4-fluoro-5-(thiophen- 2-yl)phenyl)-4-((3-(pyridin-3-yl)acrylamido)methyl)benzamide (7j) exhibit the most potent antiproliferative activity with IC50 of 3.29 and 2.59 μmol/L in Jurkat cells, respectively. Furthermore, these two compounds have a certain HDAC inhibitory activity. Collectively, the results partly encourage further development of more potential analogs based on chidamide.

Key words: chidamide, HDACs, anti-tumor activity, benzamide