Zhang Ao research group and collaborators of Shanghai Institute of medicine have made progress in the discovery and research of lead compounds against acute lung injury

Recently, Zhang Ao research group of Shanghai Institute of medicine, Chinese Academy of Sciences and Liang Guang research team of School of medicine, Wenzhou Medical University have made progress in the discovery and research of leading compounds of anti acute lung injury drugs based on natural products The research results were published on Chemical Science (DOI: 10.1039 / c9sc00086k) under the title of "biological synthesis of the natural product salviadion and its fabrics: discovery of tissue specific anti informational agents for acute lung intervention" Acute lung injury (ALI) is a kind of acute lung disease, which is clinically called respiratory distress syndrome It is known as one of the "number one killers" in intensive care unit, with a mortality rate of 30-50% The pathogenesis of Ali is complex, and there is no effective drug to treat the disease Recent studies have shown that reducing lung inflammation is a potentially effective treatment strategy Salviadione, a natural product, is a unique and novel alkaloid isolated from Salvia It is the only benzo [def] carbazole tetracycline from natural sources Due to its rare natural content (10 mg / 20 kg dried root), there are few reports on the biological activity of the natural product Inspired by its biogenic synthesis pathway, the research team first developed a new "one pot, multi-step" tandem cyclization reaction, and successfully constructed a kind of benzo [def] carbazole tetracyclic skeleton On this basis, the biomimetic synthesis of salweedone was completed with a total yield of 56% in two steps At the same time, the drug properties of salweedone were optimized based on the metabolic characteristics Finally, the leading compound with significant anti-inflammatory activity was obtained The metabolic stability and pharmacokinetic properties of liver microsomes were also improved The oral bioavailability increased from less than 1% of natural products to 30% Further study showed that the derivative was specific in lung tissue, and its selectivity was as high as 300 times compared with other tissues When oral administration of 10 mg / kg, the lead compound can selectively reduce lung inflammation, block macrophage infiltration, and then significantly alleviate LPS induced acute lung injury This study provides a new structure leading compound for the development of new safe and effective anti acute lung injury drugs Ding Chunyong, associate researcher of Shanghai Pharmaceutical Research Institute and Chen Hongjin, graduate student of Wenzhou Medical University, are the first authors of this paper The project is supported by NSFC, Ministry of science and technology and Chinese Academy of Sciences Biomimetic synthesis, derivatization, tissue distribution and anti acute lung injury activity of natural product salweedone