Download PDF
Planta Med 2019; 85(16): 1263-1274
DOI: 10.1055/a-1013-1417
Natural Product Chemistry and Analytical Studies
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Unusual Prenylated Stilbene Derivatives with PTP1B Inhibitory Activity from Artocarpus styracifolius

Wenyan Li
1   Research Center of Natural Resources of Chinese Medicinal Materials and Ethnic Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
,
Zhongji Pu
2   School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China
,
Wenfang Yi
1   Research Center of Natural Resources of Chinese Medicinal Materials and Ethnic Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
,
Qinge Ma
1   Research Center of Natural Resources of Chinese Medicinal Materials and Ethnic Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
,
Qinhua Lin
3   School of Pharmacy, Gannan Health Vocational College, Ganzhou, China
,
Guoyue Zhong
1   Research Center of Natural Resources of Chinese Medicinal Materials and Ethnic Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
,
Pengcheng Yao
1   Research Center of Natural Resources of Chinese Medicinal Materials and Ethnic Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
,
Gang Ren
1   Research Center of Natural Resources of Chinese Medicinal Materials and Ethnic Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
› Author Affiliations
Further Information

Publication History

received 29 May 2019
revised 28 August 2019

accepted 12 September 2019

Publication Date:
11 October 2019 (online)

Also available at
   Permissions and Reprints

Abstract

In an effort to identify agents from natural products that inhibit protein tyrosine phosphatase 1B (PTP1B), 5 new prenylated stilbenes, (±)-styrastilbene A (1), styrastilbene B (2), and (±)-styrastilbenes C – E (3, 4, and 7), along with 4 known structurally related compounds (5, 6, 8, and 9), were isolated from the roots of Artocarpus styracifolius. Their structures were elucidated by spectroscopic methods, including 1D and 2D nuclear magnetic resonance (NMR), high-resolution electrospray ionization mass spectrometry (HRESIMS), ultraviolet (UV), and infrared (IR). Based on these isolates, a new plausible biosynthetic pathway for the unusual stilbene derivatives 3–8 with a tetracyclic ring system is proposed. Among these compounds, 1–3, 8, and 9 displayed significant PTP1B inhibitory effects with IC50 values ranging from 2.40 (95% confidence interval [CI]: 2.21 – 2.59) to 8.80 (95% CI: 8.28 – 9.32) µM. Moreover, kinetic analysis and molecular docking simulations were performed to provide insight into the inhibition type as well as the interaction and binding mode of these active isolates with PTP1B. Our results revealed mixed-type PTP1B inhibition for all compounds tested. Docking simulations of these stilbene derivatives showed negative binding energies and close proximity to residues at the allosteric and catalytic sites of PTP1B. These findings suggest that these compounds may have a potential to be further developed as agents for the management of type 2 diabetes mellitus.

Key words

Artocarpus styracifolius - Moraceae - prenylated stilbene - diabetes - PTP1B inhibitory activity - molecular docking

Supporting Information

    The spectra (1D and 2D NMR, UV, IR, and HRESIMS) of the new compounds 1 (Fig. 1S–15S), 2 (Fig. 16S–24S), 3 (Fig. 25S–34S), 4 (Fig. 35S–47S), and 7 (Fig. 48S–58S) are available as Supporting Information.

  • Supporting Information
 

  • References

  • 1 Centers for Disease Control and Prevention (CDC). National Diabetes Statistics Report; 2017. Available at: https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf Accessed March 6, 2018
    PubMed
  • 2 World Health Organization (WHO). Diabetes Fact Sheet 312. Available at: http://www.who.int/mediacentre/factsheets/fs312/en/ Accessed August 26, 2013
    PubMed
  • 3 Cheng A, Dubé N, Gu F, Tremblay ML. Coordinated action of protein tyrosine phosphatases in insulin signal transduction. Eur J Biochem 2002; 269: 1050-1059
    CrossrefPubMedSearch in Google Scholar
  • 4 Kenner KA, Anyanwu E, Olefsky JM, Kusari J. Protein-tyrosine phosphatase 1B is a negative regulator of insulin- and insulin-like growth factor-I-stimulated signaling. J Biol Chem 1996; 271: 19810-19816
    CrossrefPubMedSearch in Google Scholar
  • 5 Comeau AB, Critton DA, Paqe R, Seto CT. A focused library of protein tyrosine phosphatase inhibitors. J Med Chem 2010; 53: 6768-6772
    CrossrefPubMedSearch in Google Scholar
  • 6 Kasibhatla B, Wos J, Peters KG. Targeting protein tyrosine phosphatase to enhance insulin action for the potential treatment of diabetes. Curr Opin Investig Drugs 2007; 8: 805-813
    PubMedSearch in Google Scholar
  • 7 Qian S, Zhang M, He Y, Wang W, Liu S. Recent advances in the development of protein tyrosine phosphatase 1B inhibitors for type 2 diabetes. Future Med Chem 2016; 8: 1239-1258
    CrossrefPubMedSearch in Google Scholar
  • 8 Eleftheriou P, Geronikaki A, Petrou A. PTP1B inhibition, a promising approach for the treatment of diabetes type II. Curr Top Med Chem 2019; 19: 246-263
    CrossrefPubMedSearch in Google Scholar
  • 9 Jagtap UB, Bapat VA. Artocarpus: a review of its traditional uses, phytochemistry and pharmacology. J Ethnopharmacol 2010; 129: 142-166
    CrossrefPubMedSearch in Google Scholar
  • 10 Zhang PZ, Gu J, Zhang GL. Novel stilbenes from Artocarpus nanchuanensis . J Asian Nat Prod Res 2015; 17: 217-223
    CrossrefPubMedSearch in Google Scholar
  • 11 Zhang XS, Wu ZY. Zhongguo Zhiwu Zhi (Flora of China). Beijing: Science Press; 1998: 40-55
    Search in Google Scholar
  • 12 Jia MR, Zhang Y. Dictionary of Chinese ethnic Medicine. Beijing: China Medical Science and Technology Press; 2016: 85-86
    Search in Google Scholar
  • 13 Ren G, Yi WF, Zhong GY, Yuan WJ, Peng JB, Ma ZL, Zeng JX. Artostyracins A–C, three new isoprenylated 2-arylbenzofurans from Artocarpus styracifolius . Phytochem Lett 2014; 10: 235-239
    CrossrefPubMedSearch in Google Scholar
  • 14 Ren G, Xiang HY, Hu ZC, Liu RH, Zhou ZW, Huang HL, Shao F, Yang M. A new isoprenylated flavone from the root bark of Artocarpus styracifolius . Biochem Syst Ecol 2013; 46: 97-100
    CrossrefPubMedSearch in Google Scholar
  • 15 Ren G, Xiang HY, Hu ZC, Liu RH, Yi WF, Peng JB, Yuan JB. Inhibitory effects of phenolic compounds from Artocarpus styracifolius on respiratory burst of rat neutrophils. Pharm Biol 2014; 52: 944-950
    CrossrefPubMedSearch in Google Scholar
  • 16 Bourjot M, Apel C, Martin MT, Grellier P, Nguyen VH, Gueritte F, Litaudon M. Antiplasmodial, antitrypanosomal, and cytotoxic activities of prenylated flavonoids isolated from the stem bark of Artocarpus styracifolius . Planta Med 2010; 76: 1600-1604
    Thieme ConnectPubMedSearch in Google Scholar
  • 17 Yu MH, Zhao T, Yan GR, Yang HX, Wang HY, Hou AJ. New isoprenylated flavones and stilbene derivative from Artocarpus hypargyreus . Chem Biodivers 2012; 9: 394-402
    CrossrefPubMedSearch in Google Scholar
  • 18 Fu DX, Chen L, Hou AJ, Yao Q, Zhang WY. Chemical constituents of Morus nigra . Chin Tradit Herbal Drugs 2005; 36: 1296-1299
    PubMedSearch in Google Scholar
  • 19 Lin CN, Lu CM, Huang PL. Flavonoids from Artocarpus heterophyllus . Phytochemistry 1995; 39: 1447-1451
    CrossrefPubMedSearch in Google Scholar
  • 20 Baderschneider B, Winterhalter P. Isolation and characterization of novel stilbene derivatives from Riesling wine. J Agric Food Chem 2000; 48: 2681-2686
    CrossrefPubMedSearch in Google Scholar
  • 21 Huang YL, Tsai WJ, Shen CC, Chen CC. Resveratrol derivatives from the roots of Vitis thunbergii . J Nat Prod 2005; 68: 217-220
    CrossrefPubMedSearch in Google Scholar
  • 22 Lineweaver H, Burk D. The determination of enzyme dissociation constants. J Am Chem Soc 1934; 56: 658-666
    CrossrefPubMedSearch in Google Scholar
  • 23 Ha MT, Seong SH, Nguyen TD, Cho WK, Ah KJ, Ma JY, Woo MH, Choi JS, Min BS. Chalcone derivatives from the root bark of Morus alba L. act as inhibitors of PTP1B and α-glucosidase. Phytochemistry 2018; 155: 114-125
    CrossrefPubMedSearch in Google Scholar
  • 24 Ha MT, Park DH, Shrestha S, Kim M, Kim JA, Woo MH, Choi JS, Min BS. PTP1B inhibitory activity and molecular docking analysis of stilbene derivatives from the rhizomes of Rheum undulatum L. Fitoterapia 2018; 131: 119-126
    CrossrefPubMedSearch in Google Scholar
  • 25 Wiesmann C, Barr KJ, Kung J, Zhu J, Erlanson DA, Shen W, Fahr BJ, Zhong M, Taylor L, Randal M, McDowell RS, Hansen SK. Allosteric inhibition of protein tyrosine phosphatase 1B. Nat Struct Mol Biol 2004; 11: 730-737
    PubMedSearch in Google Scholar
  • 26 Du Y, Ling C, Zhang M, Shen J, Li Q. Discovery of novel, potent, selective and cellular active ADC type PTP1B inhibitors via fragment-docking-oriented de novel design. Bioorg Med Chem 2015; 23: 4891-4898
    CrossrefPubMedSearch in Google Scholar
  • 27 Liu G, Xin Z, Liang H, Abad-Zapatero C, Hajduk PJ, Janowick DA, Szcepankiewicz BG, Pei Z, Hutchins CW, Ballaron SJ, Stashko MA, Lubben TH, Berg CE, Rondinone CM, Trevillyan JM, Jirousek MR. Selective protein tyrosine phosphatase 1B inhibitors: targeting the second phosphotyrosine binding site with non-carboxylic acid-containing ligands. J Med Chem 2003; 46: 3437-3440
    CrossrefPubMedSearch in Google Scholar
  • 28 Cui L, Na M, Oh H, Bae EY, Jeong DG, Ryu SE, Kim S, Kim BY, Oh WK, Ahn JS. Protein tyrosine phosphatase 1B inhibitors from Morus root bark. Bioorg Med Chem Lett 2006; 16: 1426-1429
    CrossrefPubMedSearch in Google Scholar
  • 29 Dixon M. The determination of enzyme inhibitor constants. Biochem J 1953; 55: 170-171
    CrossrefPubMedSearch in Google Scholar
  • 30 Cornish-Bowden A. A simple graphical method for determining the inhibition constants of mixed, uncompetitive and non-competitive inhibitors. Biochem J 1974; 137: 143-144
    CrossrefPubMedSearch in Google Scholar