Canthinone alkaloids are novel protein tyrosine phosphatase 1B inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 25; no. 9; pp. 1979 - 1981
• Main Authors: Sasaki, Tatsunori, Li, Wei, Higai, Koji, Koike, Kazuo
• Format: Journal Article
• Language: English
• Published: England 01.05.2015
• Subjects: Biological Products - chemistry; Biological Products - pharmacology; Carbolines - chemistry; Carbolines - pharmacology; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Hep G2 Cells; Humans; Indole Alkaloids - chemistry; Indole Alkaloids - pharmacology; Molecular Docking Simulation; Molecular Structure; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Structure-Activity Relationship; Picrasidine L; Protein tyrosine phosphatase 1B; Canthinone; Diabetes
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.03.014

Considerable attention has been paid to protein tyrosine phosphatase 1B (PTP1B) inhibitors as a potential therapy for diabetes. Screening of a natural compound library resulted in six canthinone alkaloids, namely, picrasidine L (1), 3,4-dimethyl-canthin-5,6-dione (2), 4-ethyl-3-methyl-canthin-5,6-dione (3), eurycomine E (4), 5-methoxy-canthin-6-one (5), and 5-acethoxy-canthin-6-one (6), as novel PTP1B inhibitors. Among these, 1 is the competitive PTP1B inhibitor with the best inhibitory selectivity between PTP1B and other PTPs and was shown to promote activity in the insulin signaling pathway in cell-based assays. Molecular docking simulations and structure-activity relationship analysis of 1 will add to its potential as a lead compound in future anti-insulin-resistant drug developments.