PTP1B inhibitors from stems of Angelica keiskei (Ashitaba)

Jin-Long Li; Li-Xin Gao; Fan-Wang Meng; Chun-Lan Tang; Ru-Jun Zhang; Jing-Ya Li; Cheng Luo; Jia Li; Wei-Min Zhao

doi:10.1016/j.bmcl.2015.04.003

PTP1B inhibitors from stems of Angelica keiskei (Ashitaba)

Bioorg Med Chem Lett. 2015;25(10):2028-32. doi: 10.1016/j.bmcl.2015.04.003. Epub 2015 Apr 4.

Authors

Jin-Long Li¹, Li-Xin Gao², Fan-Wang Meng³, Chun-Lan Tang², Ru-Jun Zhang¹, Jing-Ya Li², Cheng Luo⁴, Jia Li⁵, Wei-Min Zhao⁶

Affiliations

¹ Department of Natural Product Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
² National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁴ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: cluo@simm.ac.cn.
⁵ National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: jli@simm.ac.cn.
⁶ Department of Natural Product Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: wmzhao@simm.ac.cn.

PMID: 25891102
DOI: 10.1016/j.bmcl.2015.04.003

Abstract

Three new chalcones, xanthoangelols K-M (1-3), together with 19 known compounds were isolated from the stems of Angelica keiskei Koidzumi, a well-known rejuvenated and anti-diabetic plant originated from Japan. The structures of compounds 1-3 were elucidated on the basis of spectroscopic data and Mosher's method. All compounds were evaluated for their inhibitory activity against protein tyrosine phosphatase 1B (PTP1B). Among them, six chalcones, xanthoangelol K (1), xanthoangelol (4), xanthoangelol F (5), 4-hydroxyderricin (6), xanthoangelol D (7), xanthoangelol E (8), and a coumarin, methoxsalen (17), showed strong PTP1B inhibitory effect with IC50 values of 0.82, 1.97, 1.67, 2.47, 3.97, 1.43, and 2.53μg/mL, respectively. A kinetic study revealed that compound 1 inhibited PTP1B with characteristics typical of a competitive inhibitor. Molecular docking simulations elucidated that ring B of 1 may anchor in a pocket of PTP1B and the molecule is stabilized by hydrogen bonds with Arg47, Asp48, and π-π interaction with Phe182 of PTP1B.

Keywords: Angelica keiskei; Chalcone; Molecular docking; PTP1B inhibition.

Publication types

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

MeSH terms

Angelica / chemistry*
Chalcones / chemistry
Chalcones / isolation & purification*
Chalcones / metabolism
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / isolation & purification
Enzyme Inhibitors / metabolism
Hydrogen Bonding
Inhibitory Concentration 50
Japan
Models, Molecular
Plant Stems / chemistry*
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism

Substances

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