title: 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.
abstract: The transforming growth factor beta (TGFβ) signaling cascade is considered as one of the pivotal oncogenic pathways in most advanced cancers. Inhibition of the TGFβ 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-β-carboline derivatives from virtual screening which potentially inhibit the TGFβ signaling pathway. Optimization of the initial hit compound 2-benzoyl-1,3,4,9-tetrahydro-β-carboline (8a) through substitution at different positions to define the structure-activity relationship resulted in the discovery of potent inhibitors of the TGFβ 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.
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University , Shanghai 200241, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Zheng
authors.forename: Yuanzhang
authors.initials: Y
authors.lastname: Fang
authors.forename: Weiguang
authors.initials: W
authors.lastname: Tong
authors.forename: Guoliang
authors.initials: G
authors.lastname: Li
authors.forename: Haigang
authors.initials: H
authors.lastname: Wu
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhou
authors.forename: Qingxiang
authors.initials: Q
authors.lastname: Lin
authors.forename: Feifei
authors.initials: F
authors.lastname: Yang
authors.forename: Zhengfeng
authors.initials: Z
authors.lastname: Yang
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.forename: Yangrui
authors.initials: Y
authors.lastname: Peng
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Pang
authors.forename: Zhengfang
authors.initials: Z
authors.lastname: Yi
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.forename: Yihua
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002243:Carbolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009368:Neoplasm Transplantation; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D002243:Carbolines; C587719:N-phenylacetyl-1,3,4,9-tetrahydro-beta-carboline; D016212:Transforming Growth Factor beta