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

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 <b>33</b> (<b>SH498</b>) 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 <b>33</b>, 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 <b>33</b> were performed on CRC cell lines. The <i>in vivo</i> antitumor effect of <b>33</b> was also observed in HCT116 tumor-bearing mice.