Analogues of Dihydroflavonol and Flavone as Protein Tyrosine Phosphatase 1B Inhibitors from the Leaves of Artocarpus elasticus

Abstract

Protein tyrosine phosphatase 1B (PTP1B) is one of the target enzymes whose disruption leads to obesity and diabetes. A series of PTP1B inhibitors were isolated from the leaves of Artocarpus elasticus , used in traditional medicines for diabetes. The isolated inhibitors ( 1–13), including two new compounds ( 1 and 2), consisted of dihydroflavonols and flavones. The structural requirements for the PTP1B inhibitory mode and potency were revealed in both skeletons. The two highest PTP1B inhibitory properties were dihydroflavonol 1 and flavone 6 analogs with IC ₅₀ values of 0.17 and 0.79 μM, respectively. The stereochemistry also affected inhibitory potencies: trans isomer 1 (IC ₅₀= 0.17 μM) vs cis isomer 2 (IC ₅₀= 2.24 μM). Surprisingly, the dihydroflavonol and flavone glycosides ( 11 and 13) displayed potent inhibition with IC ₅₀s of 2.39 and 0.22 μM, respectively. Furthermore, competitive inhibitor 1 was applied to time-dependence experiments as a simple slow-binding inhibitor with parameters of K _i ^app = 0.064103 μM, k ₃ = 0.2262 μM ^–1 min ^–1, and k ₄ = 0.0145 min ^–1. The binding affinities by using the fluorescence quenching experiment were highly correlated with inhibitory potencies: 1 (IC ₅₀= 0.17 μM, K _SV = 0.4375 × 10 ⁵ L·mol ^–1) vs 3 (IC ₅₀= 17.79 μM, K _SV = 0.0006 × 10 ⁵ L·mol ^–1). The specific binding interactions were estimated at active and allosteric sites according to the inhibitory mode by molecular docking.