Biomimetic synthesis of dispiro sesquiterpene lactone type of alkaloids and discovery of potential anticancer scaffolds

Abstract

Herein, we developed the biomimetic synthesis of densely functionalized dispiro sesquiterpene lactone type of alkaloids via azomethine ylide cycloaddition, subsequent N-oxidation and 1,2-migration followed by a ring expansion. This successful biomimetic synthesis demonstrated that biosynthesis of sesquiterpene lactone type of alkaloids I, reported by Song and Huang, might proceed in a similar pathway. It is noteworthy that such a biomimetic synthesis strategy provides a rapid access to densely functionalized products previously inaccessible from conventional methods. Then, these newly synthesized 29 compounds were evaluated for their anticancer activity, and some compounds showed more cytotoxicity than parent compound alantolactone. The most potent compound 3j may inhibit A549 cell proliferation and induces apoptosis by triggering mitochondrial depolarization, Caspase activation, and activation of the dead receptor pathway.