新颖结构鸢尾三萜类化合物的发现与抗肿瘤活性研究

The huamn health and life is seriously threateded by malignant tumor. Novel iridal-type triterpenoids have been isolated from Belamcanda chinensis and medicinal plants of Iris. Pharmacological studies have shown that they have significant cytotoxic activity.However, it is difficult to study the microamount iridal-type triterpenoids with traditional separation strategy. In our recent study, we established the enrichment method of iridal-type triterpenoids by use of modern separate technology, and seven novel triterpenoids were isolated from rhizomes of Iris tectorum including a iridal with new carbon skeleton and significant cytotoxic acitivity. On the basis of the preliminary study, this project will focus on discovery of novel iridals-type triterpenoids with anti-tumor activity by use of established enrichment method of this kind of active ingredients and chemcial screening method (directional separate by HPLC-UV-ESIMS technology) to quickly identify trace iris-type triterpenoids from Belamcanda chinensis and medicinal plants of Iris, Iris tectorum, Iris dichotoma, Iris confusa and Iris forrestii, and the structure of isolated compounds will be determined. The isolated novel iris-type triterpenoids will be screened for anti-tumor activity. The novel iris-type triterpenoids with significant bioactivities will be selected as a template for structural modification and the structure-activity relationships will be summarized to lay the foundation for further drug research.

恶性肿瘤严重威胁人类健康与生命。中药射干和鸢尾属药用植物中含有结构新颖的鸢尾型三萜类化合物，药理研究表明它们具有显著的细胞毒活性。然而鸢尾三萜在植物中含量较低导致传统分离方法难以发现和开发。在前期研究中，我们利用现代分离技术建立了该类活性成分的富集方法，并成功从川射干根茎中发现了7个结构新颖的鸢尾三萜类化合物，其中包括一个具有较好细胞毒活性的新骨架化合物。在此基础上本项目将以发现具有抗肿瘤活性的新颖鸢尾三萜为主题，利用已建立的富集方法和快速识别化合物的化学筛选方法(通过HPLC-UV-ESIMS技术实现定向分离)，从中药射干以及鸢尾属药用植物川射干、白花射干、扁竹兰和云南鸢尾中针对性分离微量鸢尾型三萜类化合物，并测定它们的化学结构。对获得的新颖鸢尾三萜进行抗肿瘤活性筛选，选择具有明显抗肿瘤活性的鸢尾三萜为模板进行结构修饰和改造，阐明构效关系，为进一步的新药研究奠定基础。

鸢尾型三萜类化合物为鸢尾科植物所特有的化学成分，其在植物中的含量较低，属微量成分，国内外研究较少。鸢尾三萜被认为是鸢尾属植物的抗肿瘤活性成分之一。在项目实施过程中，先后完成了川射干(Iris tectorum)、中药射干(Belamcanda chinensis)、蝴蝶花（Iris japonica Thunb.）、云南鸢尾(Iris forrestii)和扁竹兰(Iris confusa)等五种药用植物的化学成分和生物活性研究。采用多种色谱分离方法，从五种植物中分离鉴定化合物219个，发现新化合物72个，其中新的鸢尾三萜类化合物63个。在已发表的新化合物中，有1个鸢尾三萜类新骨架化合物和1个鸢尾三萜异黄酮杂合体被国际天然产物权威杂志Natural Product Reports（NPR）选为热点分子,表明射干中的新颖骨架结构引起了国际学者的高度关注，也丰富了天然产物的结构类型。对分离化合物进行活性筛选，发现9个化合物具有较强的细胞毒活性，24个化合物具有较好的肝保护活性，6个化合物显示有一定的醛糖还原酶抑制活性，5个化合物表现出一定的抗氧化活性，5个化合物显示出一定的抗炎活性。在Bioorganic Chemistry、Organic&Biomolecular Chemistry、RSC Advances、Tetrahedron Letters、Phytochemistry Letters、Journal of Asian Natural Products Research等国际刊物上已发表SCI文章7篇。