2-Bromo-4′-methoxychalcone and 2-Iodo-4′-methoxychalcone Prevent Progression of Hyperglycemia and Obesity via 5′-Adenosine-Monophosphate-Activated Protein Kinase in Diet-Induced Obese Mice

Abstract

Obesity and diabetes are global health-threatening issues. Interestingly, the mechanism of these pathologies is quite different among individuals. The discovery and development of new categories of medicines from diverse sources are urgently needed for preventing and treating diabetes and other metabolic disorders. Previously, we reported that chalcones are important for preventing biological disorders, such as diabetes. In this study, we demonstrate that the synthetic halogen-containing chalcone derivatives 2-bromo-4′-methoxychalcone (compound 5) and 2-iodo-4′-methoxychalcone (compound 6) can promote glucose consumption and inhibit cellular lipid accumulation via 5′-adenosine-monophosphate-activated protein kinase (AMPK) activation and acetyl-CoA carboxylase 1 (ACC) phosphorylation in 3T3-L1 adipocytes and C2C12 skeletal myotubes. In addition, the two compounds significantly prevented body weight gain and impaired glucose tolerance, hyperinsulinemia, and insulin resistance, which collectively help to delay the progression of hyperglycemia in high-fat-diet-induced obese C57BL/6 mice. These findings indicate that 2-bromo-4′-methoxychalcone and 2-iodo-4′-methoxychalcone could act as AMPK activators, and may serve as lead compounds for a new class of medicines that target obesity and diabetes.

Mechanistic insights into dimethyl cardamonin-mediated pharmacological effects: A double control of the AMPK-HMGB1 signaling axis

“…As an AMPK activator, DMC could be useful to prevent the progression of hyperglycemia, and thus it may serve as a lead compound for a new class of drugs active against obesity and type 2 diabetes. Similar effects have been reported with structurally close chalcone derivatives such as 2-bromo- and 2-iodo-4′-methoxychalcones [ 47 ].…”

“…For example, the chalcone phloretin exhibits anticancer effects via AMPK activation [ 64 ]. Other anticancer and/or anti-inflammatory chalcone derivatives have been shown to activate AMPK, such as isoliquiritigenin [ 65 ], 2-bromo-4′-methoxychalcone [ 47 ], the prenylated chalcone xanthohumol [ 66 ], the kava chalcone flavokawain B [ 67 ] and other chalcones [ [68] , [69] , [70] ]. An interesting case is that of licochalcone A which displays antitumor and anti-inflammatory properties, like DMC [ 71 ].…”

Metabolic Impact of Flavonoids Consumption in Obesity: From Central to Peripheral

“…Several studies have demonstrated that, either from natural sources or synthetic, chalcones can impact on glucose and lipid metabolism and their health benefits have been studied in relation to type 2 diabetes [ 379 ]. Chalcones have shown hypoglycemic capacity, the ability to modulate food intake and activate AMPK, as well as antioxidant, anti-inflammatory, anticancer, anti-obesity, hepatoprotective and neuroprotective properties [ 380 , 381 , 382 , 383 , 384 , 385 , 386 , 387 , 388 , 389 , 390 , 391 , 392 ] Although there are no many studies in humans the effects of chalcones in the obese phenotype in animal models are similar to the ones described for other flavonoids, thus suggesting a potential therapeutic role of these group of bioactive compounds.…”

2-Iodo-4′-Methoxychalcone Attenuates Methylglyoxal-Induced Neurotoxicity by Activation of GLP-1 Receptor and Enhancement of Neurotrophic Signal, Antioxidant Defense and Glyoxalase Pathway

“…They are open-chain flavonoid compounds that possess a basic skeleton of A, B rings linked with α, β-unsaturated carbonyl system [14,15]. Different plant-derived types of chalcones have been isolated containing a variety of substituted elements, including methyl, methoxy and hydroxy substituents on both of the aromatic rings [16]. The most advantageous and attractive factor in producing chalcones and their derivatives are that they can be reacted via a one-step protocol using an aldol condensation between a benzaldehyde and an acetophenone in the presence of a base.…”

“…In particular, a chalcone derivative with iodo substitution at position 2 on A-ring, which never occurred in natural resources and named 2-iodo-4′-methoxychalcone (CHA79, Figure 1), has been shown to be more potent than other anti-diabetic drugs. It is noteworthy that halogen-containing chalcone derivatives are very rare in the plant kingdom, but can easily be scaled up synthetically as mentioned above [15,16]. CHA79 is suggested to act as a 5′-adenosine-monophosphate-activated protein kinase (AMPK) activator and possesses anti-diabetic activity in the literature [16].…”