Isosteviol derivatives as protein tyrosine Phosphatase-1B inhibitors: Synthesis, biological evaluation and molecular docking

Na Li; Xinyu Li; Meidi Deng; Feifei Zhu; Zian Wang; Ruilong Sheng; Wenhui Wu; Ruihua Guo

doi:10.1016/j.bmc.2023.117240

Isosteviol derivatives as protein tyrosine Phosphatase-1B inhibitors: Synthesis, biological evaluation and molecular docking

Bioorg Med Chem. 2023 Apr 1:83:117240. doi: 10.1016/j.bmc.2023.117240. Epub 2023 Mar 17.

Authors

Na Li¹, Xinyu Li¹, Meidi Deng¹, Feifei Zhu¹, Zian Wang¹, Ruilong Sheng², Wenhui Wu¹, Ruihua Guo³

Affiliations

¹ College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China.
² CQM-Centro de Química da Madeira, Campus da Penteada, Universidade da Madeira, 9000-390 Funchal, Portugal.
³ College of Food Science and Technology, Shanghai Ocean University, Shanghai 201306, China; Laboratory of Quality and Safety Risk Assessment for Aquatic Products on Storage and Preservation (Shanghai), Ministry of Agriculture, Shanghai 201306, China; Shanghai Engineering Research Center of Aquatic-Product Processing & Preservation, Shanghai 201306, China. Electronic address: rhguo@shou.edu.cn.

PMID: 36963270
DOI: 10.1016/j.bmc.2023.117240

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.

Keywords: Isosteviol derivatives; Molecular docking; PTP1B inhibitors; Structure–activity relationships; Synthesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Diabetes Mellitus, Type 2* / drug therapy
Enzyme Inhibitors / chemistry
Humans
Molecular Docking Simulation
Obesity / drug therapy
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Structure-Activity Relationship

Substances

isosteviol
Enzyme Inhibitors
Protein Tyrosine Phosphatase, Non-Receptor Type 1