Discovery of Topoisomerase I Inhibitor Nitidine Derivatives with IL-10 Enhancing Activity for the Treatment of Sepsis

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.

Keywords

Nitidine Chloride - interleukin-10 - structural modification - 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

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