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

Abstract

Herein, we developed the biomimetic synthesis of densely functionalized dispiro sesquiterpene lactone type 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 alkaloids I, reported by Song and Huang, might proceed in a similar pathway. It is noteworthy that such a biomimetic synthesis strategy provides rapid access to densely functionalized products previously inaccessible by conventional methods. The 29 newly synthesized compounds were evaluated for their anticancer activity, and some compounds showed more cytotoxicity than the parent compound alantolactone. The most potent compound 3j inhibits A549 cell proliferation and induces apoptosis by triggering mitochondrial depolarization, Caspase activation, and activation of the death receptor pathway.