Novel Podophyllotoxin Derivatives as Partial PPAR? Agonists and their Effects on Insulin Resistance and Type 2 Diabetes.

ABSTRACT: Peroxisome proliferator-activated receptor ? (PPAR?) is recognized as a key regulator of insulin resistance. In this study, we searched for novel PPAR? agonists in a library of structurally diverse organic compounds and determined that podophyllotoxin exhibits partial agonist activity toward PPAR?. Eight novel podophyllotoxin-like derivatives were synthesized and assayed for toxicity and functional activity toward PPAR? to reduce the possible systemic toxic effects of podophyllotoxin and to maintain partial agonist activity toward PPAR?. 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.

SUBMITTER: Zhang X 

PROVIDER: S-EPMC5112511 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature