Canthinone alkaloids are novel protein tyrosine phosphatase 1B inhibitors. Issue 9 (1st May 2015)

• Record Type: Journal Article
• Authors: Sasaki, Tatsunori; Li, Wei; Higai, Koji; Koike, Kazuo
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 9(2015)
• Page Start: 1979
• Page End: 1981
• Publication Date: 2015-05-01
• Subjects: Protein tyrosine phosphatase 1B -- Canthinone -- Picrasidine L -- Diabetes; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.03.014
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Six canthinone alkaloids are novel PTP1B inhibitors. Picrasidine L is the competitive PTP1B inhibitor with the best inhibitory selectivity. Picrasidine L was shown to promote activity in the insulin signaling pathway. C-4, C-9 and N-3 substitutions greatly affected PTP1B inhibitory activity. Abstract: 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 of1 will add to its potential as a lead compound in future anti-insulin-resistant drug developments.