Issue 17, 2019

Biomimetic synthesis of the natural product salviadione and its hybrids: discovery of tissue-specific anti-inflammatory agents for acute lung injury

Abstract

Acute lung injury (ALI) is an inflammatory disease with no effective pharmacological treatment. The therapeutic potential of the anti-inflammatory natural product tanshinone IIA (2) for ALI is seriously impaired by its poor pharmacokinetic (PK) properties. Inspired by the unique benzo[def]carbazole-3,5-dione (BCD) core of the natural product salviadione (5), a series of furan-fused BCD hybrids of 5 with 2 was rationally designed with the aim to improve both PK properties and the anti-inflammatory activity. A biomimetic synthetic approach featuring one-pot tandem N-heterocyclization was first developed for convenient assembly of salviadione (56% overall yield over 2 steps) and the designed hybrids (35–85% yields in one step). Compared to 2, most of the resulting compounds exhibited a markedly enhanced inhibitory effect against LPS-induced release of pro-inflammatory cytokines in macrophages. Particularly, compound 15a not only possessed the most potent activity in vitro, but also exhibited significantly improved metabolic stability (4- to 7-fold enhancement), pharmacokinetic properties (T1/2 = 4.05 h; F = 30.2%), and preferable lung tissue distribution (11- to 300-fold selectivity). An in vivo study in mice showed that pretreatment with 15a at 5 mg kg−1 distinctly attenuated LPS-induced ALI via lung tissue-specific anti-inflammatory actions, indicating that the furan-fused BCD core presents a unique chemotype with promising therapeutic potential for ALI.

Graphical abstract: Biomimetic synthesis of the natural product salviadione and its hybrids: discovery of tissue-specific anti-inflammatory agents for acute lung injury

Supplementary files

Article information

Article type
Edge Article
Submitted
07 Jan 2019
Accepted
20 Mar 2019
First published
21 Mar 2019
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2019,10, 4667-4672

Biomimetic synthesis of the natural product salviadione and its hybrids: discovery of tissue-specific anti-inflammatory agents for acute lung injury

C. Ding, H. Chen, B. Liang, M. Jiao, G. Liang and A. Zhang, Chem. Sci., 2019, 10, 4667 DOI: 10.1039/C9SC00086K

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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