Biomimetic synthesis of the natural product salviadione and its hybrids: discovery of tissue-specific anti-inflammatory agents for acute lung injury | |
Ding, Chunyong1,3; Chen, Hongjin2; Liang, Bin1; Jiao, Mingkun1; Liang, Guang2; Zhang, Ao1,3 | |
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. |
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