Selective Inhibition of PTP1B by New Anthraquinone Glycosides from Knoxia valerianoides.

Abstract

Protein tyrosine phosphatase 1B (PTP1B) is highly validated as a therapeutic target for type 2 diabetes. However, active site-directed PTP1B inhibitors generally suffer from poor selectivity and bioavailability. Inspired by the identification of a unique anthraquinone-coumarin hybrid from Knoxia valerianoides exhibiting good specificity for PTP1B over the highly homologous T-cell protein tyrosine phosphatase (TCPTP), further chemical investigation of this plant species led to the isolation of nine new anthraquinone glycosides (1-9) and two known ones (10 and 11). Structures were characterized by a combination of spectroscopic analyses and chemical methods. All compounds showed PTP1B inhibitory activities with IC50 values ranging from 1.05 to 13.74 μM. Compounds 4 and 8 exhibited greater than 64-fold selectivity over TCPTP. Enzyme kinetic studies revealed that compounds 4 and 7 behaved as mixed-type inhibitors. Docking studies predicted similar binding modes of these compounds at the allosteric site positioned between helices α3 and α6.

• Authors: Zheng Zhang, Zhi-Peng Shang, Yan Jiang, Zhao-Xia Qu, Ren-Yong Yang, Jing Zhang, Ye-Xi Lin, Feng Zhao
• Journal: Journal of natural products (J Nat Prod) Vol. 85 Issue 12 Pg. 2836-2844 (12 23 2022) ISSN: 1520-6025 [Electronic] United States
• PMID: 36399709 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Phosphoric Monoester Hydrolases
• Enzyme Inhibitors
• Anthraquinones
• Glycosides
• Protein Tyrosine Phosphatase, Non-Receptor Type 1

Topics

• Humans
• Diabetes Mellitus, Type 2 (drug therapy)
• Phosphoric Monoester Hydrolases (metabolism, therapeutic use)
• Kinetics
• Enzyme Inhibitors (pharmacology)
• Anthraquinones (chemistry)
• Glycosides (pharmacology)
• Protein Tyrosine Phosphatase, Non-Receptor Type 1
• Molecular Docking Simulation