Competitive protein tyrosine phosphatase 1B (PTP1B) inhibitors, prenylated caged xanthones from Garcinia hanburyi and their inhibitory mechanism

Abstract

Protein tyrosine phosphatase 1B (PTP1B) plays important role in diabetes, obesity and cancer. The methanol extract of the gum resin of Garcinia hanburyi (G. hanburyi) showed potent PTP1B inhibition at 10 mu g/ml. The active compounds were identified as prenylated caged xanthones (1-9) which inhibited PTP1B in dose-dependent manner. Carboxybutenyl group within caged motif (A ring) was found to play a critical role in enzyme inhibition such as 1-6 (IC(50)s = 0.47-4.69 mu M), whereas compounds having hydroxy-methylbutenyl 7 (IC50= 70.25 mu M) and methylbutenyl 8 (IC50 >200 mu M) showed less activity. The most potent inhibitor, gambogic acid 1 (IC50 = 0.47 w mu M) showed 30-fold more potency than ursolic acid (IC50 = 15.5 mu M), a positive control. In kinetic study, all isolated xanthones behaved as competitive inhibitors which were fully demonstrated with Km, V-max and K-ik/K-IV ratio. It was also proved that inhibitor 1 operated under the enzyme isomerization model having k(5) = 0.0751 mu M-1 S-1, k(6) = 0.0249 mu M-1 S-1 and K-i(app) = 0.499 mu M. To develop a pharmacophore model, we explored the binding sites of compound 1 and 7 in PTP1B. These modeling results were in agreement with our findings, which revealed that the inhibitory activities are tightly related to caged motif and prenyl group in A ring. (C) 2017 Elsevier Ltd. All rights reserved.