Pimarane Diterpenoids from the Seeds of Caesalpinia minax as PTP1B Inhibitors and Insulin Sensitizers.

Yunshao Xu,Zheling Feng,Peng Lv,Ligen Lin,Tian Zhang,Cheng Peng,Dan Li,Jun Cao

doi:10.3390/molecules25204674

Abstract

Protein-tyrosine phosphatase 1B (PTP1B) has been considered as a promising target for treating insulin resistance. In searching for naturally occurring PTB1B antagonists, two new pimarane diterpenoids, named 2α-hydroxy-7-oxo-pimara-8(9),15-diene (1) and 19-hydroxy-2α-acetoxy-7-oxo-pimara-8(9),15-diene (2), were isolated from the seeds of Caesalpinia minax. Their structures were determined by extensive analysis of NMR and HR-ESIMS data, and their absolute configurations were determined by electronic circular dichroism (ECD) spectra. Compound 1 was disclosed as a competitive inhibitor of PTP1B with an IC50 (the half-maximal inhibitory concentration) value of 19.44 ± 2.39 µM and a Ki (inhibition constant) value of 13.69 ± 2.72 μM. Moreover, compound 1 dose-dependently promoted insulin-stimulated glucose uptake in C2C12 myotubes through activating insulin signaling pathway. Compound 1 might be further developed as an insulin sensitizer.

Highlights

Protein tyrosine phosphatases (PTP) are specific, tightly regulated, and critical modulators of cellular signal initiation, transduction and termination [1]
The broad infrared (IR) absorption at 3452 cm−1 suggested the presence of hydroxy group in the structure of 1
The ultraviolet (UV) absorption maximum at 245 nm together with the insulin receptor (IR) absorption at 1742 cm−1 indicated the existence of an α,β-unsaturated ketone moiety [12]

Summary

Introduction

Protein tyrosine phosphatases (PTP) are specific, tightly regulated, and critical modulators of cellular signal initiation, transduction and termination [1]. PTP1B dephosphorylates tyrosine residues in insulin receptor (IR) and IR substrate 1 (IRS1), reducing insulin sensitivity and shutting down insulin signaling [1,2]. PTP1B dephosphorylates leptin receptor and Janus kinase 2, functioning as a negative regulator of leptin signaling [1]. PTP1B inhibitors enhance the sensitivities of insulin and leptin signaling and have favorable curing effect for diabetes and obesity [1,2]. Only two small-molecular PTP1B antagonists, ertiprotafib [3] and trodusquemine [4], have reached clinical trials, but both were failed. It is urgent to identify potent and selective small-molecular

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Conclusion