具有镇痛抗炎活性的柠檬苦素类化合物的结构改造及构效关系研究

项目名称： 具有镇痛抗炎活性的柠檬苦素类化合物的结构改造及构效关系研究

项目编号： No.21472242

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 环境科学、安全科学

项目作者： 徐云根

作者单位： 中国药科大学

项目金额： 80万元

中文摘要： 柠檬苦素广泛存在于柑橘类植物中，为高度氧化的四环三萜类化合物，具有镇痛、抗炎、抗肿瘤等活性，安全性好。但柠檬苦素的水溶性低，口服吸收差，生物利用度只有3%~14.5%，影响了其临床应用。本课题组在分析柠檬苦素结构特点的基础上，将其7位羰基成酮肟后再醚化，引入叔胺基团，得到水溶性较好的柠檬苦素类似物，发现了镇痛活性明显强于阿司匹林、抗炎活性强于萘普生的化合物XY-130322，其口服生物利用度达82.6%，显示出良好的成药性。本课题以柠檬苦素为先导化合物，采用开环、扩环、氮杂等手段，对柠檬苦素的A环、B环和D环进行结构改造，通过引入氮原子，将三萜类柠檬苦素转化为萜类生物碱，设计并合成90个类似物，通过镇痛、抗炎筛选和药代动力学研究，期望发现1至2个活性强、毒副作用低、口服吸收好、具有自主知识产权的新型镇痛抗炎候选化合物，并探索其作用机理，为柠檬苦素类化合物的进一步结构改造提供思路和理论依据。

中文关键词： 柠檬苦素；结构改造；构效关系；镇痛作用；抗炎作用

英文摘要： Limonin is highly oxygenated triterpenoids, abundant in citrus fruit and other plants found in the Rutaceae and Meliaceae family plants. Limonin exhibit a wide range of biological activities, including analgesic, anti-inflammatory and antitumor. However, limonin present poor water-solubility and low bioavailability (3%-14.5%), which greatly limit its clinical application. Based on the analysis of the structural characteristics of limonin, we modified its structure by introducing various tertiary amine moieties onto C (7)-position of limonin to yield nitrogen-containing derivatives with high solubility in water. After pharmacological screening, XY-130322 was obtained as a analgesic and anti-inflammatory candidate compounds, its analgesic activity is more potent than that of aspirin, and its anti-inflammatory activity is stronger than that of naproxen. In addition, the oral bioavailability of XY-130322 was 82.6%, which implied its good druggability. In this study, limonin was selected as the lead compound, and it's structure of A, B and D rings will be modified by means of ring opening, ring expansion and aza, etc. and thus convert limonin from triterpenoids into terpene alkaloids. A total of 90 limonin derivatives are designed and synthesized, and after analgesic, anti-inflammatory screening and pharmacokinetic studies, we expect to obtain one or two novel analgesic and anti-inflammatory candidate compounds with high potency, low toxicity, good oral absorption, and independent intellectual property rights. Meanwhile, the investigation of the mechanism for the candidate compounds may provide new ideas and theory basis in further structural modification of limonoids.

英文关键词： Limonin;Structural modification;Structure-activity Relationship;Analgesic effect;Anti-inflammatory effect