Synthesis and anticancer activities of 3-arylflavone-8-acetic acid derivatives

•Eighteen 3-arylflavone-8-acetic acid derivatives were synthesized.•All the compounds bearing methoxy groups showed higher indirect cytotoxicity than DMXAA.•Compounds 9p–r were able to induce TNF-α production in HPBMCs.•A methoxy group at the 7-position of flavones is less favorable for indirect cytotoxicity.•A methoxy group on the benzene rings is favorable for indirect cytotoxicities.

This paper describes the synthesis and the antiproliferative activities of compounds 9a–r, 3-aryl analogs of flavone-8-acetic acid that bear diverse substituents on the benzene rings at the 2- and 3-positions of the flavone nucleus. Their direct and indirect cytotoxicities were evaluated against HT-29 human colon adenocarcinoma cell lines, A549 lung adenocarcinoma cell lines and Human Peripheral Blood Mononuclear Cells (HPBMCs). The results indicate that most of the compounds bearing electron-withdrawing substituents (9b–m) exhibited moderate direct cytotoxicities. And compounds 9e and 9i showed comparable indirect cytotoxicities with 5, 6-dimethylxanthenone-4-acetic acid (DMXAA), and low direct cytotoxicities toward HPBMCs. Interestingly, the compounds 9n–r bearing methoxy groups at the 2- or 3-position of the flavone nucleus exhibited higher indirect cytotoxicities against A549 cell lines than DMXAA, and lower cytotoxicities against HPBMCs. In addition, compounds 9p–r were found to be able to induce tumor necrosis factor α (TNF-α) production in HPBMCs.

Graphical abstractThis paper describes the synthesis and antiproliferative activities of eighteen 3-arylflavone-8-acetic acid derivatives 9a–r. Among them, compounds 9p–r bearing methoxy groups showed higher indirect cytotoxicity than DMXAA and could induce TNF-α production in HPBMCs. In addition, the position of a methoxy group on the 3-arylflavone-8-acetic acid was found to have a profound impact on the indirect cytotoxicity.Figure optionsDownload full-size imageDownload as PowerPoint slide