Novel Podophyllotoxin Derivatives as Partial PPARγ Agonists and their Effects on Insulin Resistance and Type 2 Diabetes
نویسندگان
چکیده
Peroxisome proliferator-activated receptor γ (PPARγ) is recognized as a key regulator of insulin resistance. In this study, we searched for novel PPARγ agonists in a library of structurally diverse organic compounds and determined that podophyllotoxin exhibits partial agonist activity toward PPARγ. Eight novel podophyllotoxin-like derivatives were synthesized and assayed for toxicity and functional activity toward PPARγ to reduce the possible systemic toxic effects of podophyllotoxin and to maintain partial agonist activity toward PPARγ. Cell-based transactivation assays showed that compounds (E)-3-(hydroxy(3,4,5-trimethoxyphenyl)methyl)-4-(4(trifluoromethyl)styryl)dihydrofuran-2(3H)-one (3a) and (E)-4-(3-acetylstyryl)-3-(hydroxyl (3,4,5-trimethoxyphenyl)methyl)dihydrofuran-2(3H)-one (3f) exhibited partial agonist activity. An experiment using human hepatocarcinoma cells (HepG2) that were induced to become an insulin-resistant model showed that compounds 3a and 3f improved insulin sensitivity and glucose consumption. In addition, compounds 3a and 3f significantly improved hyperglycemia and insulin resistance in high-fat diet-fed streptozotocin (HFD-STZ)-induced type 2 diabetic rats at a dose of 15 mg/kg/day administered orally for 45 days, without significant weight gain. Cell toxicity testing also showed that compounds 3a and 3f exhibited weaker toxicity than pioglitazone. These findings suggested that compounds 3a and 3f improved insulin resistance in vivo and in vitro and that the compounds exhibited potential for the treatment of type 2 diabetes mellitus.
منابع مشابه
Antihyperglycemic effect of Rosa damascena is mediated by PPAR.γ gene expression in animal model of insulin resistance
Insulin resistance is a condition in which insulin signaling and action are impaired in insulin sensitive tissues and results in hyperglycemia, hyperlipidemia and type 2 diabetes mellitus. Our previous studies have shown that rosa damascena has antihyperglycemic effects on diabetic and normal rats. Therefore, we conducted a study to evaluate the effect of this medicinal plant on insulin sensiti...
متن کاملAntihyperglycemic effect of Rosa damascena is mediated by PPAR.γ gene expression in animal model of insulin resistance
Insulin resistance is a condition in which insulin signaling and action are impaired in insulin sensitive tissues and results in hyperglycemia, hyperlipidemia and type 2 diabetes mellitus. Our previous studies have shown that rosa damascena has antihyperglycemic effects on diabetic and normal rats. Therefore, we conducted a study to evaluate the effect of this medicinal plant on insulin sensiti...
متن کاملA Novel Partial Agonist of Peroxisome Proliferator-Activated Receptor γ with Excellent Effect on Insulin Resistance and Type 2 Diabetes.
Partial agonists of peroxisome proliferator-activated receptor γ (PPARγ) reportedly reverse insulin resistance in patients with type 2 diabetes mellitus. In this work, a novel non-thiazolidinedione-partial PPARγ ligand, MDCCCL1636 [N-(4-hydroxyphenethyl)-3-mercapto-2-methylpropanamide], was investigated. The compound displayed partial agonist activity in biochemical and cell-based transactivati...
متن کاملIdentification of PPARγ Agonists from Natural Sources Using Different In Silico Approaches.
Peroxisome proliferator-activated receptor γ plays an important role in lipid and glucose homeostasis and is the target of many drug discovery investigations because of its role in diseases such as type 2 diabetes. Activation of peroxisome proliferator-activated receptor γ by agonists leads to a conformational change in the ligand-binding domain altering the transcription of several target gene...
متن کاملIdentification of PPARgamma Partial Agonists of Natural Origin (I): Development of a Virtual Screening Procedure and In Vitro Validation
BACKGROUND Although there are successful examples of the discovery of new PPARγ agonists, it has recently been of great interest to identify new PPARγ partial agonists that do not present the adverse side effects caused by PPARγ full agonists. Consequently, the goal of this work was to design, apply and validate a virtual screening workflow to identify novel PPARγ partial agonists among natural...
متن کامل