1. Synthesis of Cyanoenone-Modified Diterpenoid Analogs as Novel Bmi-1-Mediated Antitumor Agents
- Author
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Wen-Wei Qiu, Jinhua Wang, Jia Xie, Wei Gao, Lian-Fang Yang, Jie-Xin Xiao, Jiuqing Xie, Xing Yajing, Zhengfang Yi, Wang Liting, and Mingyao Liu
- Subjects
0301 basic medicine ,Chemistry ,Colorectal cancer ,Organic Chemistry ,medicine.disease ,Biochemistry ,digestive system diseases ,Terpenoid ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Active compound ,Cell culture ,In vivo ,Apoptosis ,Cancer stem cell ,030220 oncology & carcinogenesis ,Drug Discovery ,Cancer research ,medicine ,PRC1 - Abstract
[Image: see text] 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 33 (SH498) 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 33, 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 33 were performed on CRC cell lines. The in vivo antitumor effect of 33 was also observed in HCT116 tumor-bearing mice.
- Published
- 2018