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

Xiangming Zhang,Yuan Qin,Ting Xiao,Bo Sun,Weilong Zhong,Cheng Yang,Xiangyan Jing,Yan Sun,Lei Zhou,Yanrong Liu,Honglei Ling,Huijuan Liu,Honggang Zhou,Tao Sun,Shuang Chen

doi:10.1038/srep37323

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.

Highlights

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone superfamily of ligand-dependent transcription factors
When incubated with HEK-293T cells co-transfected with Peroxisome proliferator-activated receptor γ (PPARγ)-ligand-binding domain (LBD), a Gal[4] chimeric expression vector, and a GAL4-responsive reporter gene plasmid, compounds 3a and 3f induced transactivation in a concentration-dependent manner, with a maximum activation equal to 50% of pioglitazone, indicating that 3a and 3f were partial agonists (Fig. 3A,B)
We searched for novel PPARγagonists in a library of structurally diverse organic compounds using the transcriptional transactivation assay and identified podophyllotoxin as a partial non-TZD PPARγligand

Summary

Introduction

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone superfamily of ligand-dependent transcription factors. The ability to retain the favorable glucose-lowering effects of partial PPARγagonists while avoiding their undesirable side effects presents a major challenge for the development of novel and safer PPARγ-based antidiabetic compounds. In the search for novel PPARγagonists, we screened a library of natural products and identified podophyllotoxin (Fig. 1), which is extracted from plants of the genus Podophyllum, and found that it exhibits partial activation of PPARγand the capacity to reverse insulin resistance. We identified two novel non-TZD derivatives as PPARγpartial agonists These derivatives are compounds 3a and 3f, chemically known as (E)-3-(hydroxy(3,4,5-trimethoxyphenyl)methyl)-4-(4-(trifluoromethyl)styryl)dihydrofuran-2(3H)-one and (E)-4-(3-acetylstyryl)-3-(hydroxyl (3,4,5-trimethoxyphenyl) methyl) dihydrofuran-2(3H)-one, respectively. These PPARγpartial agonists exhibit lower PPARγagonistic activity than pioglitazone. Surflex-Dock was used to determine the binding modes of PPARγand compounds 3a and 3f

Methods

Results

Conclusion