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. 2020 Oct 13;25(20):4674.
doi: 10.3390/molecules25204674.

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

Yunshao Xu  1 , Zheling Feng  1 , Tian Zhang  1 , Peng Lv  1 , Jun Cao  1 , Dan Li  2 , Cheng Peng  2 , Ligen Lin  1   2
Affiliations

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

Yunshao Xu et al. Molecules. .

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.

Keywords: C2C12 myotubes; Caesalpinia minax; PTP1B; glucose uptake; pimarane diterpenoids.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structures of compounds 1 and 2.
Figure 2
Figure 2
Protein-tyrosine phosphatase 1B (PTP1B) inhibitory activity and kinetic analysis for compound 1. Concentration—PTP1B inhibition ratio curves of compound 1 (A) and the positive control oleanolic acid (B). (C) Lineweaver-Burk plot for the inhibition of PTP1B by compound 1. (D) Dixon plot for the inhibition of the PTP1B by compound 1. Data are expressed as mean ± SD, n = 4.
Figure 3
Figure 3
Compound 1 enhanced insulin-stimulated glucose uptake on C2C12 myotubes through activating insulin signaling pathway. (A) Cytotoxicity of compound 1 on C2C12 myotubes when treated for 24 h by MTT assay. (B) Compound 1 increased insulin-stimulated glucose uptake on C2C12 myotubes. AICAR was used as a positive control. (C) Compound 1 activated the insulin signaling pathway in C2C12 myotubes. The expressions of p-IRS-1, IRS-1, p-Akt, Akt, and GAPDH were analyzed by Western blots. “+” means presence, and “−” means absence. Data are expressed as mean ± SD, n = 6. # p < 0.0001, control vs. insulin; * p < 0.001, compound 1 or AICAR vs. insulin.
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References

    1. Yu Z.H., Zhang Z.Y. Regulatory mechanisms and novel therapeutic targeting strategies for protein tyrosine phosphatases. Chem. Rev. 2018;118:1069–1091. doi: 10.1021/acs.chemrev.7b00105. - DOI - PMC - PubMed
    1. Maheshwari N., Karthikeyan C., Trivedi P., Moorthy N. Recent advances in protein tyrosine phosphatase 1B targeted drug discovery for type II diabetes and obesity. Curr. Drug Targets. 2018;19:551–575. doi: 10.2174/1389450118666170222143739. - DOI - PubMed
    1. Zhang Z.Y., Lee S.Y. PTP1B inhibitors as potential therapeutics in the treatment of type 2 diabetes and obesity. Expert Opin. Investig. Drugs. 2003;12:223–233. doi: 10.1517/13543784.12.2.223. - DOI - PubMed
    1. Lantz K.A., Hart S.G., Planey S.L., Roitman M.F., Ruiz-White I.A., Wolfe H.R., McLane M.P. Inhibition of PTP1B by trodusquemine (MSI-1436) causes fat-specific weight loss in diet-induced obese mice. Obesity. 2010;18:1516–1523. doi: 10.1038/oby.2009.444. - DOI - PubMed
    1. Jiang C.S., Liang L.F., Guo Y.W. Natural products possessing protein tyrosine phosphatase 1B (PTP1B) inhibitory activity found in the last decades. Acta Pharmacol. Sin. 2012;33:1217–1245. doi: 10.1038/aps.2012.90. - DOI - PMC - PubMed

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