2. Academic Validation
  3. Synthesis of Cyanoenone-Modified Diterpenoid Analogs as Novel Bmi-1-Mediated Antitumor Agents

Synthesis of Cyanoenone-Modified Diterpenoid Analogs as Novel Bmi-1-Mediated Antitumor Agents

  • ACS Med Chem Lett. 2018 Sep 27;9(11):1105-1110. doi: 10.1021/acsmedchemlett.8b00345.
Lian-Fang Yang 1,  Yajing Xing 2,  Jie-Xin Xiao 1,  Jia Xie 2,  Wei Gao 1,  Jiuqing Xie 2,  Li-Ting Wang 1,  Jinhua Wang 2,  Mingyao Liu 2,  Zhengfang Yi 2,  Wen-Wei Qiu 1
Affiliations

Affiliations

  • 1 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
  • 2 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
PMID: 30429953 DOI: 10.1021/acsmedchemlett.8b00345
Abstract

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.

Figures
Products