Synthesis of a tetra-deuterium-labeled derivative of potent and selective anticancer agent AA005

Annonaceous acetogenins are a series of potent naturally occurring anticancer agents, which act as inhibitors of complex I in mitochondria. AA005, a mimicry of acetogenins, has been found as active as those natural products and to present high selectivities between cancer and normal cells. In order to investigate the further cell-based mechanism induced by AA005, a d4-labeled derivative of AA005 (AA005-d4) was designed to detect the drug permeation ability into the membranes. In this letter, the synthesis is reported of this deuterium-labeled compound, wherein a ethylene-d4 glycol unit is incorporated efficiently into the molecule skeleton by simple etherifications.