Synthesis and Biological Evaluation of Novel Tetrahydro-β-carboline Derivatives as Antitumor Growth and Metastasis Agents through Inhibiting the Transforming Growth Factor-β Signaling Pathway

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• 作者：Cong Zheng ; Yuanzhang Fang ; Weiguang Tong ; Guoliang Li ; Haigang Wu ; Wenbo Zhou ; Qingxiang Lin ; Feifei Yang ; Zhengfeng Yang ; Peng Wang ; Yangrui Peng ; Xiufeng Pang ; Zhengfang Yi ; Jian Luo ; Mingyao Liu ; Yihua Chen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：February 13, 2014
• 年：2014
• 卷：57
• 期：3
• 页码：600-612
• 全文大小：872K
• ISSN：1520-4804

文摘

The transforming growth factor beta (TGF尾) signaling cascade is considered as one of the pivotal oncogenic pathways in most advanced cancers. Inhibition of the TGF尾 signaling pathway by specific antagonists, neutralizing antibodies, or small molecules is considered as an effective strategy for the treatment of tumor growth and metastasis. Here we demonstrated the identification of a series of tetrahydro-尾-carboline derivatives from virtual screening which potentially inhibit the TGF尾 signaling pathway. Optimization of the initial hit compound 2-benzoyl-1,3,4,9-tetrahydro-尾-carboline (8a) through substitution at different positions to define the structure鈥揳ctivity relationship resulted in the discovery of potent inhibitors of the TGF尾 signaling pathway. Among them, compound 8d, one of the tested compounds, not only showed potent inhibition of lung cancer cell proliferation and migration in vitro but also strongly suppressed growth of lung cancer and breast cancer in vivo.