Annonaceous Acetogenins: The Hydroxyl Groups and THF Rings Are Crucial Structural Elements for Targeting the Mitochondria, Demonstration with the Synthesis of Fluorescent Squamocin Analogues

Abstract

suspected of being linked to com-plex I inhibition.The intriguingly highly potent biological properties coupledwith a lack of clear structure–activity relationship studies estab-lishing the exact role of each distinctive part of the acetoge-nins, prompted us to initiate a program directed towards thesynthesis of hybrids consisting of an acetogenin tail connectedto a fluorescent tag. In this context, information from such de-rivatives should shine light on the role of the hydroxyl/THFpart of these natural products as a specific (or not) recognitionsite directed towards mitochondrial internal membranes.Squamocin, isolated from Annona reticulata seeds, waschosen as a starting material for the hemisynthesis of our fluo-rescent analogues. Our laboratory has previously described anefficient ruthenium-catalyzed periodic oxidation of the terminallactone of squamocin 1 that enabled the formation of a car-boxylic acid–squamocin derivative 2 (Scheme 1),