Design, Synthesis, and Antitumor Activity of Novel Eupatilin Derivatives Based on the Mannich Reaction.

Abstract

Eupatilin, a natural bioactive flavone, is the active ingredient in traditional Chinese medicine Artemisia argyi Levl. et Vant. To enhance the antitumor effect of eupatilin, we designed a series of novel eupatilin-Mannich derivatives and investigated antitumor activity against several human cancer cell lines, including gastric cancer cells (AGS), esophageal cancer cells (Eca-109), and breast cancer cells (MDA-MB-231). Among all derivatives, the majority demonstrated superior antitumor activity compared to eupatilin, with compound 3d exhibiting the most effective antitumor activity against AGS cells. Furthermore, compound 3d effectively inhibited colony formation and migration of AGS cells. Network pharmacology combined with molecular docking studies indicated that compound 3d exerts antitumor activity by targeting the Hsp90AA1 and multiple signaling pathways. In addition, the Western blot experiment results showed that compound 3d reduced the expression of Hsp90AA1 in AGS cells, indicating that Hsp90AA1 may be the potential target of compound 3d. In summary, several novel eupatilin derivatives were prepared via the Mannich reaction, representing the first structure modification study of eupatilin. The mechanism of action of compound 3d was estimated through cell experiments, network pharmacology, molecular docking, and Western blot experiments, to provide lead compounds for the discovery of natural product-based antitumor candidates.