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DOI: 10.1055/s-0044-1780496
Discovery of Topoisomerase I Inhibitor Nitidine Derivatives with IL-10 Enhancing Activity for the Treatment of Sepsis
Funding This work was supported by the Three-year Action Plan for Shanghai TCM Development and Inheritance Program (Grant No. ZY [2021-2023]-0401) and Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (Grant No. ZYYCXTD-D-202004).
![](https://www.thieme-connect.de/media/10.1055-s-00043364/202401/lookinside/thumbnails/10-1055-s-0044-1780496_2300056-1.jpg)
Abstract
Nitidine chloride (NC) is a natural product that promotes the expression of interleukin-10 (IL-10) in macrophages by inhibiting topoisomerase I (TopoI) under stimulation by lipopolysaccharides (LPSs) and can be used in the treatment of sepsis. However, NC's poor water solubility limits its applications. This study aimed to design and synthesize a series of derivatives by simplifying the A- and E-rings in the structure of NC and introducing oxygen-containing groups, using NC as the lead compound. In this work, the ability of NC and its derivatives to induce IL-10 secretion and inhibit TopoI was evaluated. The water solubility of the compounds was determined in phosphate-buffered saline. An LPS-induced sepsis in mice was prepared to assess the activity of the compounds in vivo. Our data suggested that compound 6F showed better activity in inducing IL-10 secretion and inhibiting TopoI, and its water solubility was at least 500-fold higher than that of NC. When septic mice were given 6F (3 mg/kg), their survival rate was comparable to those treated with NC. Based on our findings, 6F may be a new drug candidate for the treatment of sepsis.
Supporting Information
Spectral data (1H NMR and 13C NMR) for compounds 2A–6A, 2B, 3B, 5B, 6B, 2C, 3C, 5C, 6C, 2D–6D, 2E–8E, 2F–6F, 6G, 8G, 9G, and 2H–7H are included in this Supporting Information ([Figs. S1–S39]) (available in the online version).
# These authors contributed equally to this work.
Publication History
Received: 13 October 2023
Accepted: 29 January 2024
Article published online:
07 March 2024
© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
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