Novel Podophyllotoxin Derivatives as Partial PPARγ Agonists and their Effects on Insulin Resistance and Type 2 Diabetes

Abstract

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.

CMHX008, a PPARγ partial agonist, enhances insulin sensitivity with minor influences on bone loss

“…Several natural or synthetic PPARγ partial agonists retained similar antidiabetic effects as rosiglitazone but showed minimized side effects, such as weight gain. 22 , 30 , 32 , 33 , 34 Consistent with these findings, CMHX008 showed a similar efficacy as rosiglitazone in ameliorating glucose homeostasis in HFD or ob/ob mice in the absence of weight gain. We also observed increased oxygen consumption and carbon dioxide production as measured by indirect calorimetry, suggesting that CMHX008, similar to other PPARγ partial agonists, such as GQ-16, shared similar improving effects on the metabolic rate with rosiglitazone.…”

PEGylated Graphene Oxide as a Nanodrug Delivery Vehicle for Podophyllotoxin (GO/PEG/PTOX) and In Vitro α-Amylase/α-Glucosidase Inhibition Activities

“… 22 Hybrid molecules with improved selectivity and reduced side effects could enhance the potent action of PTOX. Some of its derivatives have been found to improve insulin resistance and hyperglycemia in type-2 diabetic conditions; 23 however, the role of PTOX in type-2 diabetes, especially, the core enzymes which play an important role in diabetes mellitus remedy, has not yet been established. There has been no report available on the α-amylase/α-glucosidase inhibitory activities of PTOX or GO surface-coated PTOX; hence, this study was performed to formulate GO/PEG/PTOX nanocomposites without using DCC and so forth to evaluate their α-amylase/α-glucosidase inhibitory potential.…”

Circular RNA circCSPP1 promotes the occurrence and development of colon cancer by sponging miR-431 and regulating ROCK1 and ZEB1

“…Colon cancer is a common malignant tumor of the digestive tract, and its incidence is ranked third among gastrointestinal tumors [ 1 ]. Over the past few decades, the rapid development of molecular biology has enriched the theory of colorectal cancer carcinogenesis [ 1 – 4 ]. In addition, immense progress has been made in diagnostic and treatment strategies for colorectal cancer; the 5-year survival rate of patients with localized disease is 90.1% [ 5 ].…”