Soluble epoxide hydrolase inhibitors of indolinone alkaloids and phenolic derivatives from Cimicifuga dahurica (Turcz.) Maxim.

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Abstract

The aim of this study was to search for potential therapeutic agents by identifying novel inhibitors of soluble epoxide hydrolase (sEH) from natural plants using an in silico approach. We found that an ethanolic extract from the roots of Cimicifuga dahurica (Turcz.) Maxim. significantly inhibited sEH in vitro. In a phytochemical investigation using assay-guided fractionation of the dichloromethane extract of C. dahurica, we isolated two new indolinone alkaloids (5 and 6) and five related constituents (1–4, and 7) and established their structures based on an extensive analysis using 1D and 2D NMR, and MS methods. All of the isolated compounds inhibited sEH enzymatic activity in a dose-dependent manner, with IC50 values ranging from 0.8 ± 0.0 to 2.8 ± 0.4 μM. A kinetic analysis of compounds 1–7 revealed that compound 2 was non-competitive; 1, 3, and 7 were mixed-type; and 4–6 were competitive inhibitors. Molecular docking was employed to further elucidate their receptor-ligand binding characteristics. These results demonstrated that compounds from C. dahurica are potential sEH inhibitors.

Section snippets

Conclusions

This study identified the structures of two new indolinone alkaloid derivatives (5 and 6) and five related constituents (1–4 and 7) from C. dahurica using spectroscopic data analysis and chemical methods. Seven compounds from this plant exhibited sEH inhibitory activity, with IC50 values ranging from 0.8 ± 0.0 to 2.8 ± 0.4 μM. The results of kinetic analysis confirmed that compounds 1, 3, and 7 are mixed-type inhibitors, compound 2 is a non-competitive inhibitor, and compounds 4–6 are competitive

Acknowledgments

This study was supported by the Priority Research Center Program (2009-0093815) through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology, Republic of Korea.

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