Inhibition of protein tyrosine phosphatase 1B (PTP1B) and alpha-glucosidase by xanthones from Cratoxylum cochinchinense, and their kinetic characterization

Abstract

Cratoxylum cochinchinense displayed significant inhibition against protein tyrosine phosphatase 1B (PTP1B) and alpha-glucosidase, both of which are key target enzymes to attenuate diabetes and obesity. The compounds responsible for both enzymes inhibition were identified as twelve xanthones (1-12) among which compounds 1 and 2 were found to be new ones. All of them simultaneously inhibited PTP1B with IC(50)s of (2.4-52.5 mu M), and alpha-glucosidase with IC50 values of (1.7-72.7 mu M), respectively. Cratoxanthone A (3) and c-mangostin (7) were estimated to be most active inhibitors against both PTP1B (IC50 = 2.4 mu M for 3, 2.8 mu M for 7) and alpha-glucosidase (IC50 = 4.8 mu M for 3, 1.7 mu M for 7). In kinetic studies, all isolated xanthones emerged to be mixed inhibitors of alpha-glucosidase, whereas they behaved as competitive inhibitors of PTP1B. In time dependent experiments, compound 3 showed isomerization inhibitory behavior with following kinetic parameters: K-i(app) = 2.4 mu M; k(5) = 0.05001 mu M-1 S-1 and k(6) = 0.02076 mu M-1 S-1. (C) 2017 Elsevier Ltd. All rights reserved.