Synthesis of Rottlerone Analogues and Evaluation of Their α-Glucosidase and DPP-4 Dual Inhibitory and Glucose Consumption-Promoting Activity.

Yinan Zhang,Xue Zhao,Zhihong Yan,Robert H Dodd,Hua Sun,Haibo Wang,Peng Yu,Kui Lu,Yan Wu

doi:10.3390/molecules26041024

Abstract

Our previous study found that desmethylxanthohumol (1) inhibited α-glucosidase in vitro. Recently, further investigations revealed that dehydrocyclodesmethylxanthohumol (2) and its dimer analogue rottlerone (3) exhibited more potent α-glucosidase inhibitory activity than 1. The aim of this study was to synthesize a series of rottlerone analogues and evaluate their α-glucosidase and DPP-4 dual inhibitory activity. The results showed that compounds 4d and 5d irreversibly and potently inhibited α-glucosidase (IC50 = 0.22 and 0.12 μM) and moderately inhibited DPP-4 (IC50 = 23.59 and 26.19 μM), respectively. In addition, compounds 4d and 5d significantly promoted glucose consumption, with the activity of 5d at 0.2 μM being comparable to that of metformin at a concentration of 1 mM.

Highlights

Diabetes mellitus is a multi-gene metabolic disease that is characterized by hyperglycemia that is caused by a relative (Type 2 Diabetes) or absolute (Type 1 Diabetes) insulin deficiency
The inhibition of digestive α-glucosidase is one therapeutic approach to slowing down carbohydrate digestion and glucose absorption, thereby stabilizing blood glucose level and preventing hyperglycemia in diabetic patients. α-Glucosidase inhibitors have become a better choice in the case of Asian diabetic patients that are associated with high consumption of carbohydrates in their staple diet [4]
Dipeptidyl peptidase-4 (DPP4) inhibitors enhance the plasma level of active glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which results in increased insulin

Summary

Introduction

Diabetes mellitus is a multi-gene metabolic disease that is characterized by hyperglycemia that is caused by a relative (Type 2 Diabetes) or absolute (Type 1 Diabetes) insulin deficiency. Α-Glucosidase plays an important role in the physiological process of postprandial digestion and the absorption of carbohydrates in food in patients with Type 2 Diabetes, and it is the key enzyme involved in the hydrolysis of dietary carbohydrates [3]. The inhibition of digestive α-glucosidase is one therapeutic approach to slowing down carbohydrate digestion and glucose absorption, thereby stabilizing blood glucose level and preventing hyperglycemia in diabetic patients. Α-Glucosidase inhibitors have become a better choice in the case of Asian diabetic patients that are associated with high consumption of carbohydrates in their staple diet [4]. Dipeptidyl peptidase-4 (DPP4) inhibitors enhance the plasma level of active glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which results in increased insulin

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Conclusion