CN: 32-1845/R
ISSN: 2095-6975
Cite this paper:
ZHANG Xiang-Yu, LI Wei, WANG Jian, LI Ning, CHENG Mao-Sheng, KOIKE Kazuo. Protein tyrosine phosphatase 1B inhibitory activities of ursane-type triterpenes from Chinese raspberry, fruits of Rubus chingii[J]. Chinese Journal of Natural Medicines, 2019, 17(1): 15-21

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

ZHANG Xiang-Yu1,3, LI Wei1,2, WANG Jian1,3, LI Ning1, CHENG Mao-Sheng1,3, KOIKE Kazuo2
1 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China;
2 Faculty of Pharmaceutical Sciences, Toho University, Chiba 274-8510, Japan;
3 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
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.
Key words:    Protein tyrosine phosphatase 1B    Raspberry    Rubus chingii    Triterpene    Ursane   
Received: 2018-08-20   Revised:
PDF (2603 KB) Free
Print this page
Email this article to others
Articles by ZHANG Xiang-Yu
Articles by LI Wei
Articles by WANG Jian
Articles by LI Ning
Articles by CHENG Mao-Sheng
Articles by KOIKE Kazuo
[1] Byon CHJ, Kusari BA, Kusari J. Protein-tyrosine phosphatase-1B acts as a negative regulator of insulin signal transduction[J]. Mol Cell Biochem, 1998, 182(1-2):101-108.
[2] Kennedy BP. Role of protein tyrosine phosphatase-1B in diabetes and obesity[J]. Biomed Pharmacother, 1999, 53(10):466-470.
[3] Elchebly M, Payette P, Michaliszyn E, et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene[J]. Science, 1999, 283(5407):1544-1548.
[4] Bentires AM, Neel BG. Protein-tyrosine phosphatase 1B is required for HER2/Neu-induced breast cancer[J]. Cancer Res, 2007, 67(6):2420-2424.
[5] Zhang S, Zhang ZY. PTP1B as a drug target:recent developments in PTP1B inhibitor discovery[J]. Drug Discov Today, 2007, 12(9-10):373-381.
[6] Yip SC, Saha S, Chernoff J. PTP1B:a double agent in metabolism and oncogenesis[J]. Trends Biochem Sci, 2010, 35(8):442-449.
[7] Erbe DV, Wang S, Zhang YL, et al. Ertiprotafib improves glycemic control and lowers lipids via multiple mechanisms[J]. Mol Pharmacol, 2005, 67(1):69-77.
[8] Lantz KA, Hart SG, Planey SL, et al. Inhibition of PTP1B by trodusquemine (MSI-1436) causes fat-specific weight loss in diet-induced obese mice[J]. Obesity, 2010, 18(8):1516-1523.
[9] Combs AP. Recent advances in the discovery of competitive protein tyrosine phosphatase 1B inhibitors for the treatment of diabetes, obesity, and cancer[J]. J Med Chem, 2010, 53(6):2333-2344.
[10] Su XH, Duan R, Sun YY, et al. Cardiovascular effects of ethanol extract of Rubus chingii Hu (Rosaceae) in rats:an in vivo and in vitro approach[J]. J Physiol Pharmacol, 2014, 65(3):417-424.
[11] Zhang TT, Wang M, Yang L, et al. Flavonoid glycosides from Rubus chingii Hu fruits display anti-inflammatory activity through suppressing MAPKs activation in macrophages[J]. J Func Foods, 2015, 18:235-243.
[12] Zeng HJ, Liu Z, Wang YP, et al. Studies on the anti-aging activity of a glycoprotein isolated from Fupenzi (Rubus chingii Hu.) and its regulation on klotho gene expression in mice kidney[J]. Int J Biol Macromol, 2018, 119, 470-476.
[13] Hattori M, Kuo KP, Shu YZ, et al. A triterpene from the fruits of Rubus chingii[J]. Phytochemistry, 1988, 27(12):3975-3976.
[14] Zhong R, Guo Q, Zhou G, et al. Three new labdane-type diterpene glycosides from fruits of Rubus chingii and their cytotoxic activities against five humor cell lines[J]. Fitoterapia, 2015, 102:23-26.
[15] Onoda T, Li W, Sasaki T, et al. Identification and evaluation of magnolol and chrysophanol as the principle protein tyrosine phosphatase-1B inhibitory compounds in a Kampo medicine, Masiningan[J]. J Ethnopharmacol, 2016, 186:84-90.
[16] Sasaki T, Li W, Higai K, et al. Canthinone alkaloids are novel protein tyrosine phosphatase 1B inhibitors[J]. Bioorg Med Chem Lett, 2015, 25(9):1979-1981.
[17] Sasaki T, Li W, Higai K, et al. Protein tyrosine phosphatase 1B inhibitory activity of lavandulyl flavonoids from roots of Sophora flavescens[J]. Planta Med, 2014, 80(7):557-560.
[18] Li W, Li S, Higai K, et al. Evaluation of licorice flavonoids as protein tyrosine phosphatase 1B inhibitors[J]. Bioorg Med Chem Lett, 2013, 23(21):5836-5839.
[19] Sasaki T, Li W, Morimura H, et al. Chemical constituents from Sambucus adnata and their protein-tyrosine phosphatase 1B inhibitory activities[J]. Chem Pharm Bull, 2011, 59(11):1396-1399.
[20] Gnoatto SC, Dassonville-Klimpt A, Da Nascimento S, et al. Evaluation of ursolic acid isolated from Ilex paraguariensis and derivatives on aromatase inhibition[J]. Eur J Med Chem, 2008, 43(9):1865-1877.
[21] Jia Z, Liu X, Liu Z. Triterpenoids from Sanguisorba alpine[J]. Phytochemistry, 1992, 32(2):155-159.
[22] Taniguchi S, Imayoshi Y, Kobayashi E, et al. Production of bioactive triterpenes by Eriobotrya japonica calli[J]. Phytochemistry, 2002, 59(3):315-323.
[23] Li D, Li W, Higai K, et al. Protein tyrosine phosphatase 1B inhibitory activities of ursane-and lupane-type triterpenes from Sorbus pohuashanensis[J]. J Nat Med, 2014, 68(2):427-431.
[24] Tabernero L, Aricescu AR, Jones EY, et al. Protein tyrosine phosphatases:structure-function relationships[J]. FEBS J, 2008, 275(5):867-882.

Related Articles:
1. MEI Yu-Dan, ZHANG Nan, ZHANG Wei-Yang, TANG Jin-Shan, ZHOU Hua, YU Yang, YAO Xin-Sheng.Two new ursane-type nortriterpenes from Lonicera macranthoides and their iNOS-inhibitory activities[J]. Chinese Journal of Natural Medicines, 2019,17(1): 27-32