Biomimetic synthesis of the natural product salviadione and its hybrids: discovery of tissue-specific anti-inflammatory agents for acute lung injury
| العنوان: | Biomimetic synthesis of the natural product salviadione and its hybrids: discovery of tissue-specific anti-inflammatory agents for acute lung injury |
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| المؤلفون: | Chunyong Ding, Mingkun Jiao, Guang Liang, Ao Zhang, Chen Hongjin, Bin Liang |
| المصدر: | Chemical Science |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Natural product, 010405 organic chemistry, medicine.drug_class, General Chemistry, Lung injury, Pharmacology, respiratory system, 010402 general chemistry, 01 natural sciences, In vitro, Anti-inflammatory, 0104 chemical sciences, chemistry.chemical_compound, Chemistry, chemistry, Pharmacokinetics, In vivo, Biomimetic synthesis, medicine, Distribution (pharmacology) |
| الوصف: | Biomimetic synthesis of the natural product salviadione and its hybrids was achieved leading to tissue-specific anti-inflammatory agents for acute lung injury. 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. |
| تدمد: | 2041-6520 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1de8ae6c7c2c74620e7f8dfcd41ae936Test https://pubmed.ncbi.nlm.nih.gov/31123577Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....1de8ae6c7c2c74620e7f8dfcd41ae936 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20416520 |
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