Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 9, Issue 11, Pages 1105-1110Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.8b00345
Keywords
Diterpenoid; cyanoenone; antitumor; colorectal cancer; Bmi-1
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Funding
- Shanghai Science and Technology Council [18ZR1411200]
- National Natural Science Foundation of China [81472788, 81773204]
- Major State Basic Research Development Program of China [2015CB910400]
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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.
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