ABSTRACT
Protein tyrosine phosphatase (PTP1B) antagonizes insulin signaling and acts as a potential therapeutic target for insulin resistance associated with obesity and type II diabetes. In this work, a series of isosteviol derivatives 1-28 was synthesized and the inhibitory activity on PTP1B was evaluated by double antibody sandwich ELISA (DAS-ELISA) in vitro. Most isosteviol derivatives showed moderate PTP1B inhibitory activities. Among them, derivatives 10, 13, 24, 27 showed remarkable bioactivities with IC50 values ranging from 0.24 to 0.40 µM. Particularly, derivative 24 exhibited the best inhibitory activity against PTP1B (IC50 = 0.24 µM) in vitro; moreover, it showed 7-fold selectivity to PTP1B over T-cell protein tyrosine phosphatase (TCPTP) and 14-fold selectivity to PTP1B over cell division cycle 25 homolog B (CDC25B). Molecular docking studies demonstrated the hydrogen bond interaction between 24 and LYS-116 residue in PTP1B might be essential for the inhibitory activity. The results suggested that derivative 24 has great potential to be employed as drug candidate for the treatment of obesity and type II diabetes.
