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 (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.