Design, synthesis, and preliminary bioactivity evaluation of 2,7-substituted carbazole derivatives as potent autotaxin inhibitors and antitumor agents
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. Method: 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.
Anti-Cancer Agents in Medicinal Chemistry
Wang, W., Zhao, F., Zhao, Y., Pan, W., Cao, P., Wu, L., Wang, Z., & Zhao, X. (2019). Design, synthesis, and preliminary bioactivity evaluation of 2,7-substituted carbazole derivatives as potent autotaxin inhibitors and antitumor agents. Anti-Cancer Agents in Medicinal Chemistry, 19 (2), 256-264. https://doi.org/10.2174/1871520618666180830161821