3-硫（硒）代吲哚的高效合成和抗炎活性研究

Sepsis is a systemic acute inflammatory response syndrome and is the leading cause of death in the clinical ICU. In recent years, although a few compounds that have effective treatment on sepsis have been found, they have not been used clinically due to many deficiencies such as poor druggability and poor selectivity. 3-Substituted indole is a class of important anti-inflammatory active molecular parent nucleus, many drugs which contain 3-substituted indole structure have been used to treat inflammatory diseases in clinic. In the previous work, we found that 3-arylthioindole and 3-arylselenoindole compounds can effectively inhibit the release of many inflammatory factors which are induced by LPS, and further developed a method that efficiently synthesizes different kinds of 3-chacogenyl indoles. In this project, we will synthesize different kinds of 3-chacogenyl indoles and establish compound libraries on the basis of previous work, discover anti-inflammatory active candidate drugs through in vitro and in vivo anti-inflammatory activity experiments, pharmacological experiments, druggability experiments, and ultimately explore anti-inflammatory pharmacological targets using protein chip technology and related experiments. The successful implementation of this project will provide new research ideas for the design and development of sepsis drugs.

脓毒血症是全身性急性炎性反应综合征，是临床ICU主要致死原因。近些年来，虽然有少数可有效治疗脓毒血症的化合物先后被发现，但因成药性差、选择性弱等诸多缺陷，导致最终无法进入临床应用。3-取代吲哚是一类重要的抗炎活性分子母核，临床已有多种3-取代吲哚类药物应用于炎症性疾病的治疗。前期工作中，我们发现3-芳基硫醚吲哚和3-芳基硒醚吲哚类化合物可有效抑制LPS诱导的多种炎症因子的释放，并进一步发展了可高效合成不同种类的3-硫（硒）代吲哚的合成方法。本项目中，我们将在此基础上合成不同种类的3-硫（硒）代吲哚并建立化合物库，通过体内外抗炎活性实验、药理学实验、成药性实验等，发现抗炎活性候选药物，并最终利用蛋白芯片技术和相关实验探寻抗炎药理作用靶点。本项目的顺利实施将为治疗脓毒血症药物的设计和研发提供新的研究思路。

急性炎性疾病会导致局部或系统的炎症，是特护病房中致死率极高的疾病。最近的研究表明，抑制炎症因子的过度产生是预防和治疗此类疾病最有效的策略之一。然而，现有的可有效抑制炎症因子释放的抗炎药物在治疗该类疾病的试验中因疗效低、存在副反应等诸多缺陷，导致最终无法进入临床应用。前期研究中，我们发现硫代吲哚和硒代吲哚类化合物可有效抑制脂多糖诱导的多种炎症因子的释放。本项目中，我们设计并合成了54个不同种类的硫代吲哚类化合物和硒代吲哚类化合物。通过体外抗炎活性测试得到了3b、3o、3u和3ab四个抗炎活性好的候选化合物。急性肺损伤模型小鼠体内实验证明，化合物3o可有效降低肺湿干比，TNF-a和IL-6在肺泡灌洗液和血清中的含量；改善肺组织病理学变化；抑制促炎因子的转录水平。随后，我们合成了生物素标记的活性化合物，利用蛋白芯片技术对活性化合物的靶蛋白进行了探索研究。本课题的系列研究发展了温和条件下高效合成硫（硒）吲哚的新方法，发现了新型抗炎先导化合物。这些结果将为抗炎新药的设计和研发提供新的研究思路。