氰基烯酮修饰的二萜类似物作为新型Bmi-1介导的抗肿瘤剂的合成
Synthesis of Cyanoenone-Modified Diterpenoid Analogs as Novel Bmi-1-Mediated Antitumor Agents.
作者信息
Yang Lian-Fang, Xing Yajing, Xiao Jie-Xin, Xie Jia, Gao Wei, Xie Jiuqing, Wang Li-Ting, Wang Jinhua, Liu Mingyao, Yi Zhengfang, Qiu Wen-Wei
机构信息
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
出版信息
ACS Med Chem Lett. 2018 Sep 27;9(11):1105-1110. doi: 10.1021/acsmedchemlett.8b00345. eCollection 2018 Nov 8.
Bmi-1 is overexpressed in colorectal cancer (CRC) and served as a novel therapeutic target for the treatment of CRC. A series of novel cyanoenone-modified diterpenoid analogs was synthesized and investigated for their antiproliferative activity against CRC cells. The results showed that most of these compounds exhibited potent antiproliferative and Bmi-1 inhibitory activity. Among them, the most active compound () showed more potent antiproliferative activity than the positive control compound PTC-209. These synthetic diterpenoid analogs were less toxic for normal human fibroblasts (HAF) than for CRC cells. Especially , its selectivity index (SI) between HAF and tumor cells was 7.3-13.1, which was much better than PTC-209. The polycomb repressive complex 1 (PRC1) complex, transwell migration, colony formation, cancer stem cell proliferation, and apoptosis assays of were performed on CRC cell lines. The antitumor effect of was also observed in HCT116 tumor-bearing mice.
Bmi-1在结直肠癌（CRC）中过表达，并作为CRC治疗的新靶点。合成了一系列新型氰基烯酮修饰的二萜类类似物，并研究了它们对CRC细胞的抗增殖活性。结果表明，这些化合物大多表现出强大的抗增殖和Bmi-1抑制活性。其中，活性最强的化合物（）显示出比阳性对照化合物PTC-209更强的抗增殖活性。这些合成的二萜类类似物对正常人成纤维细胞（HAF）的毒性低于对CRC细胞的毒性。特别是，其在HAF和肿瘤细胞之间的选择性指数（SI）为7.3-13.1，远优于PTC-209。在CRC细胞系上进行了多梳抑制复合物1（PRC1）复合物、Transwell迁移、集落形成、癌症干细胞增殖和凋亡分析。在荷HCT116肿瘤小鼠中也观察到了的抗肿瘤作用。
Zotero 插件