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

doi:10.1039/c9sc00086k

	Biomimetic synthesis of the natural product salviadione and its hybrids: discovery of tissue-specific anti-inflammatory agents for acute lung injury
	Ding, Chunyong 1,3; Chen, Hongjin 2; Liang, Bin 1; Jiao, Mingkun 1; Liang, Guang 2; Zhang, Ao 1,3
刊名	CHEMICAL SCIENCE
	2019-05-07
卷号	10 期号:17 页码:4667-4672
ISSN号	2041-6520
DOI	10.1039/c9sc00086k
通讯作者	Liang, Guang() ; Zhang, Ao(aozhang@simm.ac.cn)
英文摘要	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 (T-1/2 = 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 tissuespecific anti-inflammatory actions, indicating that the furan-fused BCD core presents a unique chemotype with promising therapeutic potential for ALI.
资助项目	National Natural Science Foundation of China[21877120] ; National Natural Science Foundation of China[81430080] ; National Program on Key Basic Research Project of China[2015CB910603] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002-010-001] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020374]
WOS关键词	RESPIRATORY-DISTRESS-SYNDROME ; TANSHINONE-IIA ; DERIVATIVES ; ABSORPTION
WOS研究方向	Chemistry
语种	英语
出版者	ROYAL SOC CHEMISTRY
WOS记录号	WOS:000465940700011
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/289909]
专题	中国科学院上海药物研究所
通讯作者	Liang, Guang; Zhang, Ao
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 2.Wenzhou Med Univ, Sch Pharmaceut Sci, Chem Biol Res Ctr, Wenzhou 325035, Zhejiang, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Ding, Chunyong,Chen, Hongjin,Liang, Bin,et al. Biomimetic synthesis of the natural product salviadione and its hybrids: discovery of tissue-specific anti-inflammatory agents for acute lung injury[J]. CHEMICAL SCIENCE,2019,10(17):4667-4672.
APA	Ding, Chunyong,Chen, Hongjin,Liang, Bin,Jiao, Mingkun,Liang, Guang,&Zhang, Ao.(2019).Biomimetic synthesis of the natural product salviadione and its hybrids: discovery of tissue-specific anti-inflammatory agents for acute lung injury.CHEMICAL SCIENCE,10(17),4667-4672.
MLA	Ding, Chunyong,et al."Biomimetic synthesis of the natural product salviadione and its hybrids: discovery of tissue-specific anti-inflammatory agents for acute lung injury".CHEMICAL SCIENCE 10.17(2019):4667-4672.