Design, Synthesis, and Preliminary Bioactivity Evaluation of 2,7-Substituted Carbazole Derivatives as Potent Autotaxin Inhibitors and Antitumor Agents

作者：Wang, Wenming; Zhao, Fengmei; Zhao, Yarui; Pan, Weiwei; Cao, Pengcheng; Wu, Lintao; Wang, Zhijun; Zhao, Xuan; Zhao, Yi; Wang, Hongfei^*

来源：Anti-Cancer Agents in Medicinal Chemistry, 2019, 19(2): 256-264.

DOI：10.2174/1871520618666180830161821

• Autotaxin
• carbazole derivatives
• phosphodiesterase inhibitor
• cytotoxicity
• anticancer drug
• molecular docking

Background: Autotaxin-LPA signaling has been implicated in cancer progression, and targeted for the discovery of cancer therapeutic agents. @@@ Objective: Potential ATX inhibitors were synthesized to develop novel leading compounds and effective anti-cancer agents. @@@ Methods: The present work designs and synthesizes a series of 2,7-subsitituted carbazole derivatives with different terminal groups R [R = -CI (I), -COOH (II), -B(OH)(2) (III), or -PO(OH)(2) (I-IV)]. The inhibition of these compounds on the enzymatic activity of ATX was measured using FS-3 and Bis-pNpp as substrates, and the cytotoxicity of these compounds was evaluated using SW620, SW480, PANC-1, and SKOV-3 human carcinoma cells. Furthermore, the binding of leading compound with ATX was analyzed by molecular docking. @@@ Results: Compound III was shown to be a promising antitumor candidate by demonstrating both good inhibition of ATX enzymatic activity and high cytotoxicity against human cancer cell lines. Molecular docking study shows that compound III is located in a pocket, which mainly comprises amino acids 209 to 316 in domain 2 of ATX, and binds with these residues of ATX through van der Waals, conventional hydrogen bonds, and hydrophobic interactions. @@@ Conclusion: Compound III with the terminal group R = -B(OH)(2) has the most potent inhibitory effect with the greatest cytotoxicity to cancer cells. Moreover, the docking model provides a structural basis for the future optimization of promising antitumor compounds.

• 出版日期2019
• 单位山西大学; 长治学院