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

Publication date: Available online 6 March 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Xue Fei Tan, Zia Uddin, Chanin Park, Yeong Hun Song, Minky Son, Keun Woo Lee, Ki Hun Park
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 µg/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 (IC50s = 0.47- 4.69 µM), whereas compounds having hydroxymethylbutenyl 7 (IC50 = 70.25 µM) and methylbutenyl 8 (IC50 >200 µM) showed less activity. The most potent inhibitor, gambogic acid 1 (IC50 = 0.47 µM) showed 30-fold more potency than ursolic acid (IC50 = 15.5 µM), a positive control. In kinetic study, all isolated xanthones behaved as competitive inhibitors which were fully demonstrated with Km, Vmax and Kik/Kiv ratio. It was also proved that inhibitor 1 operated under the enzyme isomerization model having k5 = 0.0751 µM^-1S^-1, k6 = 0.0249 µM^-1S^-1 and Ki^app = 0.499 µM. 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.

Graphical abstract

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