Structure defines bioactivity of avocado-derived acetogenins

The chapter will focus on the diverse structure and the vast spectrum of mechanisms of action of the lauraceaous acetogenins, a group of avocado-derived aliphatic alcohols that are 17, 19, or 21 carbon atoms in length. In the avocado, these lipids may occur as free alcohols or esterified to acetyl groups while possessing hydroxyl or carbonyl groups and double or triple unsaturations. The chapter will focus on the studies comparing the efficacy of these natural products and their structural analogues against various metabolic diseases, including malignancies and insulin resistance. The avocado-derived acetogenins avocatin-B (Avo-B) and persin are two of the most thoroughly studied acetogenins, with published structure-activity relationships linking their structure to the modulation of mitochondrial metabolism, which will constitute a major focus of this chapter. Avo-B consists of a 1:1 mixture of two 17-carbon long fatty alcohols, avocadene and avocadyne, with hydroxyl groups at C-2 and C-4; the only structural difference between the constituents is a terminal unsaturation with a double or triple bond present for avocadene or avocadyne, respectively. Abnormally high rates of mitochondrial fatty acid oxidation (FAO) are a hallmark feature of both diet-induced obesity (DIO) and acute myeloid leukemia (AML); Avo-B is a potent FAO inhibitor, resulting in the amelioration of insulin resistance in DIO and selective AML death. A recently published structure-activity study by our group determined that the odd number of carbon atoms, the presence and stereochemistry of the (2R,4R)-configuration, and terminal unsaturation are critical for FAO modulation. Persin is an acetylated 21-carbon long fatty alcohol with a hydroxyl group at C-2 and a keto group at C-4, as well as double bonds at C-12 and C-15. In breast cancer, persin was recently found to stabilize microtubules; activation of mitochondria led to apoptosis and was dependent on the expression of the mitochondrial protein Bim, a member of the BH3-only protein that modulates cell death. While the loss of the C-12 and C-15 double bonds was inconsequential, a recently published structure-activity study determined that shortening the length of the aliphatic linear chain, having an (2S)-stereochemistry, or esterification of sterically hindered phenolic groups to the structure of persin resulted in the complete loss of antibreast cancer activity. The review will thus discuss the diverse structure-activity relationships of avocado-derived fatty alcohols with a focus on well-elucidated compounds with a molecular target to highlight their potential preclinical efficacy.