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

Author(s): Wenming Wang, Fengmei Zhao, Yarui Zhao, Weiwei Pan, Pengcheng Cao, Lintao Wu, Zhijun Wang, Xuan Zhao, Yi Zhao*, Hongfei Wang*.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry

Volume 19 , Issue 2 , 2019

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Graphical Abstract:


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 anticancer agents.

Methods: The present work designs and synthesizes a series of 2,7-subsitituted carbazole derivatives with different terminal groups R [R = -Cl (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.

Keywords: Autotaxin, carbazole derivatives, phosphodiesterase inhibitor, cytotoxicity, anticancer drug, molecular docking.

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Year: 2019
Page: [256 - 264]
Pages: 9
DOI: 10.2174/1871520618666180830161821
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