Protein tyrosine phosphatase 1B inhibitory activities of ursane-type triterpenes from Chinese raspberry, fruits of Rubus chingii
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摘要
Protein tyrosine phosphatase 1 B(PTP1 B) 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 PTP1 B inhibitory activity. Further bioactivity-guided fractionation resulted in the isolation of three PTP1 B 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 PTP1 B inhibitor, and 2 and 3 were mixed type PTP1 B 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-acetoxyurs-12-ene-28-oic acid(5), and pomolic acid-3β-acetate(6) bound at the allosteric site including α3, α6, and α7 helix of PTP1 B.
Protein tyrosine phosphatase 1 B(PTP1 B) 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 PTP1 B inhibitory activity. Further bioactivity-guided fractionation resulted in the isolation of three PTP1 B 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 PTP1 B inhibitor, and 2 and 3 were mixed type PTP1 B 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-acetoxyurs-12-ene-28-oic acid(5), and pomolic acid-3β-acetate(6) bound at the allosteric site including α3, α6, and α7 helix of PTP1 B.
Protein tyrosine phosphatase 1 B(PTP1 B) 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 PTP1 B inhibitory activity. Further bioactivity-guided fractionation resulted in the isolation of three PTP1 B 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 PTP1 B inhibitor, and 2 and 3 were mixed type PTP1 B 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-acetoxyurs-12-ene-28-oic acid(5), and pomolic acid-3β-acetate(6) bound at the allosteric site including α3, α6, and α7 helix of PTP1 B.
引文
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[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 1Binhibitory 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 1Binhibitory 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 1Binhibitory 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.
[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].JFunc 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 1Binhibitory 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 1Binhibitory 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 1Binhibitory 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.