Protein tyrosine phosphatase 1B inhibitory activities of ursane-type triterpenes from Chinese raspberry, fruits of Rubus chingii

Xiang-Yu Zhang; Wei Li; Jian Wang; Ning Li; Mao-Sheng Cheng; Kazuo Koike

doi:10.1016/S1875-5364(19)30004-4

Protein tyrosine phosphatase 1B inhibitory activities of ursane-type triterpenes from Chinese raspberry, fruits of Rubus chingii

Chin J Nat Med. 2019 Jan;17(1):15-21. doi: 10.1016/S1875-5364(19)30004-4.

Authors

Xiang-Yu Zhang¹, Wei Li², Jian Wang³, Ning Li⁴, Mao-Sheng Cheng¹, Kazuo Koike⁵

Affiliations

¹ Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
² Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; Faculty of Pharmaceutical Sciences, Toho University, Chiba 274-8510, Japan. Electronic address: liwei@phar.toho-u.ac.jp.
³ Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: jianwang@syphu.edu.cn.
⁴ Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
⁵ Faculty of Pharmaceutical Sciences, Toho University, Chiba 274-8510, Japan.

PMID: 30704618
DOI: 10.1016/S1875-5364(19)30004-4

Abstract

Protein tyrosine phosphatase 1B (PTP1B) has led to an intense interest in developing its inhibitors as anti-diabetes, anti-obesity and anti-cancer agents. The fruits of Rubus chingii (Chinese raspberry) were used as a kind of dietary traditional Chinese medicine. The methanolic extract of R. chingii fruits exhibited significant PTP1B inhibitory activity. Further bioactivity-guided fractionation resulted in the isolation of three PTP1B inhibitory ursane-type triterpenes: ursolic acid (1), 2-oxopomolic acid (2), and 2α, 19α-dihydroxy-3-oxo-urs-12-en-28-oic acid (3). Kinetics analyses revealed that 1 was a non-competitive PTP1B inhibitor, and 2 and 3 were mixed type PTP1B inhibitors. Compounds 1-3 and structurally related triterpenes (4-8) were further analyzed the structure-activity relationship, and were evaluated the inhibitory selectivity against four homologous protein tyrosine phosphatases (TCPTP, VHR, SHP-1 and SHP-2). Molecular docking simulations were also carried out, and the result indicated that 1, 3-acetoxy-urs-12-ene-28-oic acid (5), and pomolic acid-3β-acetate (6) bound at the allosteric site including α3, α6, and α7 helix of PTP1B.

Keywords: Protein tyrosine phosphatase 1B; Raspberry; Rubus chingii; Triterpene; Ursane.

MeSH terms

Enzyme Inhibitors / chemistry
Enzyme Inhibitors / metabolism*
Fruit / chemistry
Humans
Kinetics
Methanol / chemistry
Molecular Docking Simulation
Molecular Structure
Plant Extracts / chemistry
Protein Binding
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
Protein Tyrosine Phosphatases / antagonists & inhibitors
Rubus / chemistry*
Structure-Activity Relationship
Triterpenes / chemistry
Triterpenes / metabolism*

Substances

Enzyme Inhibitors
Plant Extracts
Triterpenes
ursane
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Protein Tyrosine Phosphatases
Methanol