乙酰氧苯甲酸黄杞苷酯的合成及其抗肺纤维化作用中对lncRNA的调控机制研究

The incidence of pulmonary fibrosis increases year by year due to environmental pollution. Pulmonary fibrosis is a group of pulmonary interstitial disease pathogenesis unclearly, which has the typical feature of high mortality and short mean survival with no cure. So it is very important clinical value to look for drugs and drug targets for effective prevention and treatment of pulmonary fibrosis. Huang qi glycosides is the active ingredient obtained from plant roots glabrous greenbrier rhizome by our team. But huang qi glycosides there are A, B, C ring in a plane, molecular accumulation is close due to the presence of intermolecular and intramolecular hydrogen bond, and limit the sugar ring rotation of the molecules to assume molecular structure rigidity and the poor solubility in the water. The existence of the multiple phenolic hydroxyl also leads to the easy oxidation discoloration. We make huang qi glycosides as the mother nucleus, conduct a series of optimization of structure transformation, and get a new compound named acetyl oxygen benzoate huang qi glycosides ester. Preliminary.pharmacological activities analysis shows that the compound has stronger resistance to pulmonary fibrosis. The project team propose to optimize the further process for making the chemical compound and have a deeper study the role of this chemical compound in the ceRNA regulatory network of long non-coding RNA BC161882, which will provide theoretical basis for developing effective medicines for lung fibrosis and reveal its molecular target.

间质性肺疾病是一组发病机制不明的疾病谱，以肺间质性纤维化为特征，病死率高，近年来发病率逐年上升，目前仍无有效治疗药物。黄杞苷是本项目组从植物根茎土茯苓中分离得到的活性成分，但是黄杞苷分子中A、B、C三环处于近似一个平面内，分子堆积紧密，由于分子间与分子内氢键的存在，限制了分子中糖环的旋转，使分子呈刚性结构，溶性差。另外多个酚羟基的存在也导致其易氧化变色。本课题组以黄杞苷为母核进行了一系列的优化结构改造，其中以乙酰氧苯甲酸取代黄杞苷中的鼠李糖得到的新化合物（命名为乙酰氧苯甲酸黄杞苷酯）的活性更强、稳定性更好并具有良好的成药性。本项目拟进一步优化乙酰氧苯甲酸黄杞苷酯的制备工艺，探讨该化合物抗肺纤维化的作用及其对长链非编码RNA-BC161882的ceRNA网络调控机制，为开发肺纤维化的治疗药物及其药物作用靶点提供数据。

肺纤维化是一种弥漫性间质性肺疾病，是各种原因所致肺部疾病的创伤愈合反应，主要表现为肺泡结构紊乱和结缔组织过度沉积，最终导致不可逆的呼吸功能衰竭，好发于60岁之上的人群。近年来随着我国步入老龄化社会，发病率逐年上升，目前尚无有效治疗药物。该项目以黄杞苷和乙酰氧苯甲酸为原料，用化学结构修饰的方法制备新的化合物，项目组命名为乙酰氧苯甲酸黄杞苷酯（Acetyl oxygen benzoate engeletin ester, AOBEE），通过体内外肺纤维化模型，研究该化合物具有显著的抗肺纤维化的作用。在此基础上，以lncRNA为切入点，从组织形态学、基因表达调控、基因信息学等方面，利用基因转染、基因干扰等技术明确了该化合物在肺纤维化发生中以lnc865和lnc556为核心的ceRNA调控网络，为开发肺纤维化新药和lncRNA作为药物作用靶点提供了重要的理论基础和可靠的实验数据。