旋覆花抗哮喘倍半萜内酯衍生物合成、构效关系及作用机制研究

Bronchial asthma (asthma) is a common disease which is a chronic airway inflammation by a variety of inflammatory cells, such as mast cells, eosinophils and T lymphocytes. In our previous research, it was found that sesquiterpene lactones in Inula japonica effectively inhibited degranulation and leukotriene generation in mast cells. The 1,6-O,O-diacetylbritannilactone showed excellent activity. It had a different chemical structure and mechanism with the market anti-asthma drugs. Ten derivatives of 1,6-O,O-diacetylbritannilactone were synthesized. Most derivatives’ activity was enhanced five folds. It was showed that the 1,6-O,O-diacetylbritannilactone was a valuable lead compound. This project is about the study of the derivative synthesis, and structure-activity relationship of lead compound. The in vitro mechanism of excellent derivatives was further researched. This research also could provide the candidate compounds for the discovery of anti-inflammatory and anti-asthma drugs.

支气管哮喘(哮喘)是当今世界最常见的一种疾病，是由多种炎症细胞特别是肥大细胞、嗜酸性粒细胞和T淋巴细胞参与的慢性气道炎症。本课题前期发现旋覆花倍半萜内酯类成分能有效地抑制肥大细胞脱颗粒和白三烯生成，其中以1,6-O,O-二乙酰基旋覆花内酯活性最为突出，其化学结构与作用机制均不同于上市的抗哮喘药物。进一步合成了10个1,6-O,O-二乙酰基旋覆花内酯衍生物，部分衍生物的活性比原天然产物提高了5倍，表明1,6-O,O-二乙酰基旋覆花内酯是很有价值的先导化合物。在此基础上，本课题以该先导化合物为模板，进行衍生合成和构效关系研究，并以细胞生物学实验手段体外研究强活性衍生物的作用机制，为抗炎抗哮喘新药研发提供候选化合物。

哮喘通常情况下表现为慢性气道炎症，其发病过程和包括一氧化氮和白三烯在内的诸多炎症因子密切相关。本项目以1,6-O,O-乙酰基大花旋覆花内酯为先导化合物进行了结构优化，合成了各种衍生物59个，完成了对巨噬细胞一氧化氮生成抑制和肥大细胞LTC4生成抑制作用的筛选。构效关系分析表明，芳基取代异恶唑啉螺内酯为抑制肥大细胞白三烯生成的核心结构。本研究进一步合成了15个倍半萜内酯螺异恶唑啉衍生物，其中化合物ABL-51抑制肥大细胞白三烯生成的活性最强（IC50=71.21 nM），较先导化合物的活性水平提高了近80倍。. 进一步对ABL-51的抗炎作用分子机制研究表明，ABL-51下调Akt通路和MAPK通路关键信号分子（Akt, p38, ERK, cPLA2）的磷酸化水平，进而抑制白三烯生成并发挥抗炎作用。ABL-51的小鼠急性毒性实验结果显示，其最大耐受剂量为2000 mg/kg；药代动力学表明，ABL-51吸收速度快，代谢也较快，生物利用度偏低。本项目发现了具有新骨架倍半萜内酯螺异恶唑啉衍生物，是抗炎抗哮喘的新药候选化合物。.