Discovery of Anthraquinones as DPP-IV Inhibitors: Structure-Activity Relationships And Inhibitory Mechanism

Abstract

Dipeptidyl peptidase-IV (DPP-IV) is a kind of serine protease, which is a well-known key therapeutic and preventive target for type II diabetes. The development of DPP-IV inhibitors is one of the main directions of drug research for the treatment of diabetes at present. In this study, we investigated the inhibitory effects and mechanisms of a series of anthraquinones on DPP-IV in human plasma using fluorescence-based biochemical assays. The results showed that multiple anthraquinones could significantly inhibit the activity of DPP-IV, and alizarin (AQ7), aloe emodin (AQ11), emodin (AQ13) emerged the outstanding inhibitory potential with IC50 values lower than 5 μM. Inhibition kinetics and molecular docking demonstrated that both alizarin red S (AQ8) and AQ13 were effective noncompetitive inhibitors of DPP-IV, while AQ7, alizarin complexone (AQ9), AQ11, rhein (AQ12), anthraquinone-2-carboxylic acid (AQ23) represent as mixed inhibitors. SAR demonstrated that hydroxyl group at C-1 and C-8 sites and hydroxyl, hydroxymethyl or carboxyl group at the C-2 or C-3 site were very essential for DPP-IV inhibition, replacement of hydroxyl group with amino group at C-1 could led to an increase of the inhibitory potential. Further investigations demonstrated that both compound AQ7 and AQ13 could inhibit the expression of DPP-IV on living cells level. Taken together, the inhibitory effect of anthraquinones elucidated in this study not only yields benefits for the research and development of highly effective inhibitors of DPP-IV with anthraquinones as the lead compounds, but also facilitates to better understanding the pharmacologic efficiency and the value of clinical applications of natural anthraquinones.

Keywords: Anthraquinones, inhibitors, dipeptidyl peptidase-IV, inhibition mechanism, type II diabetes