Protein phosphatases are considered a target for drug-based therapy because of their involvement in cell signaling pathways linked to type II diabetes, obesity, and some cancers. Protein tyrosine phosphatase 1B (PTP1B) functions as a negative regulator of the insulin pathway, and as such, is considered a target for anti-diabetic therapy. A gene knockout study in mice showed that the absence of this enzyme caused an increase in insulin sensitivity. High conservation across the active site of non-receptor class I subfamily of phosphatases has made finding specific inhibitors difficult; competitive inhibitors have been unsuccessful in clinical trials due to undesirable interactions with other phosphatases. Several classes of natural product substructures as potential inhibitors for PTP1B were explored, with the goal of identifying a molecular scaffold to generate site-specific inhibitors. Chalcone, stilbene, and flavonoid derivatives have been shown to be PTP1B inhibitors. Therefore, we have synthesized an array of derivatives to observe the effects of hydrogen bonding patterns and electronic characteristics on inhibition. Preliminary <i>in silico </i>modeling data suggest favorable thermodynamic interactions between potential inhibitors and PTP1B. Furthermore, activity assays showed some of the synthetic compounds were comparable to the natural products as inhibitors. Structural trends correlated with results from molecular docking simulations and the combination of enzymatic assays and modeling were used to inform the selection of a new library of novel derivatives.

Synthesis and evaluation of chalcone, stilbene, and flavonoid Inhibitors of protein tyrosine phosphatase 1B

ACS Spring 2022

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