Design and synthesis of tricyclic terpenoid derivatives as novel PTP1B inhibitors with improved pharmacological property and in vivo antihyperglycaemic efficacy

Abstract

2020) Design and synthesis of tricyclic terpenoid derivatives as novel PTP1B inhibitors with improved pharmacological property and in vivo ABSTRACT Overexpression of protein tyrosine phosphatase 1B (PTP1B) induces insulin resistance in various basic and clinical research. In our previous work, a synthetic oleanolic acid (OA) derivative C10a with PTP1B inhibitory activity has been reported. However, C10a has some pharmacological defects and cytotoxicity. Herein, a structure-based drug design approach was used based on the structure of C10a to elaborate the smaller tricyclic core. A series of tricyclic derivatives were synthesised and the compounds 15, 28 and 34 exhibited the most PTP1B enzymatic inhibitory potency. In the insulin-resistant human hepatoma HepG2 cells, compound 25 with the moderate PTP1B inhibition and preferable pharmaceutical properties can significantly increase insulin-stimulated glucose uptake and showed the insulin resistance ameliorating effect. Moreover, 25 showed the improved in vivo antihyperglycaemic potential in the nicotinamide-streptozotocin-induced T2D. Our study demonstrated that these tricyclic derivatives with improved molecular architectures and antihyperglycaemic activity could be developed in the treatment of T2D. GRAPHICAL ABSTRACT ARTICLE HISTORY

Application of Terpenoid Compounds in Food and Pharmaceutical Products

“…[76]; in terms of the role of the respiratory system, andrographolide has a certain anti-upper respiratory tract infection effect, and menthone has anti-asthmatic, expectorant, cough-suppressant and other effects; for the nervous system, some terpenoids have the effects of sedation, analgesia, local anesthesia, central excitation and neurolysis. In terms of anti-tumor effects, paclitaxel has a good effect on breast cancer and ovarian cancer, and some terpenoid derivatives attempt to treat liver cancer [77].…”