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.
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氰烯酮修饰二萜类似物作为新型 Bmi-1 介导的抗肿瘤药物的合成
DOI：
10.1021/acsmedchemlett.8b00345
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发表时间：
2018-09
影响因子：
4.2
通讯作者：
Qiu Wen-Wei
中科院分区：
文献类型：
--
作者：
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
Bmi-1 在结直肠癌 (CRC) 中过度表达，可作为治疗 CRC 的新治疗靶点。合成了一系列新型氰烯酮修饰的二萜类似物，并研究了它们对结直肠癌细胞的抗增殖活性。结果表明，大多数这些化合物表现出有效的抗增殖和 Bmi-1 抑制活性。其中，最活跃的化合物33（SH498）显示出比阳性对照化合物PTC-209更有效的抗增殖活性。这些合成的二萜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。尤其是33，其HAF与肿瘤细胞之间的选择性指数（SI）为7.3-13.1，明显优于PTC-209。对 CRC 细胞系进行了 33 种多梳抑制复合物 1 (PRC1) 复合物、跨孔迁移、集落形成、癌症干细胞增殖和凋亡测定。在HCT116荷瘤小鼠中也观察到33的体内抗肿瘤作用。
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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影响因子：
5.4
作者：
Zhang Z;Bu X;Chen H;Wang Q;Sha W
通讯作者：
Sha W
影响因子：
11.2
作者：
N. Suh;A. Roberts;Stephanie Birkey Reffey;K. Miyazono;S. Itoh;P. ten Dijke;E. Heiss;A. Place;R. Risingsong;Charlotte R. Williams;T. Honda;G. Gribble;M. Sporn
通讯作者：
N. Suh;A. Roberts;Stephanie Birkey Reffey;K. Miyazono;S. Itoh;P. ten Dijke;E. Heiss;A. Place;R. Risingsong;Charlotte R. Williams;T. Honda;G. Gribble;M. Sporn
影响因子：
15
作者：
STORK, G;BURGSTAHLER, AW
通讯作者：
BURGSTAHLER, AW
DOI：
10.1016/b978-1-4160-3251-9.50008-x
发表时间：
2019-10
期刊：
The Lancet
影响因子：
--
作者：
E. Dekker;P. Tanis;J. Vleugels;P. Kasi;M. Wallace
通讯作者：
E. Dekker;P. Tanis;J. Vleugels;P. Kasi;M. Wallace
影响因子：
2
作者：
Xiaohua Gao;D. Deeb;J. Hao;Yongbo Liu;A. Arbab;S. Dulchavsky;S. Gautam
通讯作者：
Xiaohua Gao;D. Deeb;J. Hao;Yongbo Liu;A. Arbab;S. Dulchavsky;S. Gautam