Design, synthesis and biological activity of piperlongumine derivatives as selective anticancer agents

•Sixteen piperlongumine derivatives were prepared in five or six steps.•2-Halogen piperlongumines showed moderate in vitro activity against four cancer cells.•Most of the compounds showed modest selectivity for lung normal cells.•Halogen substituents at C2 played an important role in increasing cytotoxicity.

In an effort to expand the structure–activity relationship of the natural anticancer compound piperlongumine, we have prepared sixteen novel piperlongumine derivatives with halogen or morpholine substituents at C2 and alkyl substituents at C7. Most of 2-halogenated piperlongumines showed potent in vitro activity against four cancer cells and modest selectivity for lung normal cells. The highly active anticancer compound 11h exhibited obvious ROS elevation and excellent in vivo antitumor potency with suppressed tumor growth by 48.58% at the dose of 2 mg/kg. The results indicated that halogen substituents as electrophilic group at C2 played an important role in increasing cytotoxicity.

Graphical abstractSixteen piperlongumine derivatives with halogen or morpholine at C2 and alkyl substituents at C7 were prepared as anticancer agents. The highly active anticancer compound 11h exhibited obvious ROS elevation and excellent in vivo antitumor potency.Figure optionsDownload full-size imageDownload as PowerPoint slide