Oleanolic acid indole derivatives as novel α-glucosidase inhibitors: Synthesis, biological evaluation, and mechanistic analysis
Date of Original Version
Research efforts have been directed to the development of oleanolic acid (OA) based α-glucosidase inhibitors and various OA derivatives showed improved anti-α-glucosidase activity. However, the inhibitory effects of indole infused OA derivatives on α-glucosidase is unknown. Herein, we synthesized a series of indole-OA (2a-2o) and -OA methyl ester (3a-3 l) derivatives with various electron withdrawing groups inducted to indole benzene ring and evaluated their anti-α-glucosidase activity. Indole OA derivatives (2a-2o) exhibited superior α-glucosidase inhibitory effects as compared to OA methyl ester derivatives (3a-3l) and OA (with IC50 values of 4.02 μM-5.30 μM v.s. over 10 μM and 5.52 µM, respectively). In addition, mechanistic studies using biochemical (kinetic assay), biophysical (circular dichroism), and computational (docking) methods revealed that OA-indole derivatives (2a and 2f) are mixed type of α-glucosidase inhibitors and their inhibitory effects were attributed to their capacity of forming the ligand-enzyme complex with α-glucosidase enzyme. Findings from this study support that OA indole derivatives are promising α-glucosidase inhibitors as a potential management of diabetes mellitus.
Wu, Panpan, Hao He, Hang Ma, Borong Tu, Jiahao Li, Shengzhu Guo, Silin Chen, Nana Cao, Wende Zheng, Xiaowen Tang, Dongli Li, Xuetao Xu, Xi Zheng, Zhaojun Sheng, Weiqian David Hong, and Kun Zhang. "Oleanolic acid indole derivatives as novel α-glucosidase inhibitors: Synthesis, biological evaluation, and mechanistic analysis." Bioorganic Chemistry 107, (2021). doi:10.1016/j.bioorg.2020.104580.