Amorfrutins are potent antidiabetic dietary natural products

Abstract

Given worldwide increases in the incidence of obesity and type 2 diabetes, new strategies for preventing and treating metabolic diseases are needed. The nuclear receptor PPARγ (peroxisome proliferator-activated receptor gamma) plays a central role in lipid and glucose metabolism; however, current PPARγ-targeting drugs are characterized by undesirable side effects. Natural products from edible biomaterial provide a structurally diverse resource to alleviate complex disorders via tailored nutritional intervention. We identified a family of natural products, the amorfrutins, from edible parts of two legumes, Glycyrrhiza foetida and Amorpha fruticosa, as structurally new and powerful antidiabetics with unprecedented effects for a dietary molecule. Amorfrutins bind to and activate PPARγ, which results in selective gene expression and physiological profiles markedly different from activation by current synthetic PPARγ drugs. In diet-induced obese and db/db mice, amorfrutin treatment strongly improves insulin resistance and other metabolic and inflammatory parameters without concomitant increase of fat storage or other unwanted side effects such as hepatoxicity. These results show that selective PPARγ-activation by diet-derived ligands may constitute a promising approach to combat metabolic disease.nuclear receptors | nutrition | compound screening | organic synthesis | x-ray structure

Bavachinin, as a novel natural pan-PPAR agonist, exhibits unique synergistic effects with synthetic PPAR-γ and PPAR-α agonists on carbohydrate and lipid metabolism in db/db and diet-induced obese mice

“…Mouse studies conclude that BVC displays properties desired for a glucoselowering pan-PPAR agonist. Previous studies have indicated that full agonism of PPAR-γ, as with RSG and PGZ, may be responsible for the side effects associated with glucoselowering effects [37][38][39]. Therefore, BVC does not cause weight gain and hepatotoxicity because of its submaximal activation of PPAR-γ and additional activation of PPAR-α and -β/δ.…”

Total synthesis of amorfrutin B via a Pd-catalyzed regioselective geranyl migration-decarboxylation-cycloaromatization cascade

“…11 Recently this family of natural products has been discovered to exhibit antidiabetic activities. 12 More specifically, amorfrutin B was identified as a partial agonist of peroxisome proliferator-activated receptor γ (PPARγ) with a considerably higher affinity and γ-selectivity than that of any other amorfrutins previously reported, and similar to that of the marketed drug rosiglitazone. 13 Due to its physiological profiles remarkably different from current marketed PPARγ drugs, and the predictable application prospects, this compound has found extensive research interest in many labs, for example, in pharmacodynamic and structure-activity relationship studies.…”

“…12 The geranyl moiety could be introduced by electrophilic aromatic alkylation with geraniol in the presence of BF 3 -OEt 2 as catalyst or by using regioselective metalation of the 2-position with n-BuLi or KH and subsequent alkylation with geranyl bromide or chloride. 13,15,18 However, yields were typically low, with co-production of considerable amounts of O-geranylated product.…”

PPAR-gamma Signaling in Metabolic Homeostasis

“…It was not surprising if there are many significant research efforts to explore the PPAR-γ activating potential of a wide range of natural products originating from medicinal plants. (53) PPAR-γ-ligands used to often identified in plants that are common food sources, including the tea plant, soybeans, palm oil, ginger, and grapes. The presence of PPAR-γ ligands in food products warrants an exploration whether this nuclear receptor may be effectively activated by the intake of nutraceuticals, by consumption of functional foods or by dietary supplements.…”