三种吴茱萸属植物中新型吲哚喹唑啉生物碱的发现及其抗真菌活性研究

项目名称： 三种吴茱萸属植物中新型吲哚喹唑啉生物碱的发现及其抗真菌活性研究

项目编号： No.31470425

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 冯煦

作者单位： 江苏省中国科学院植物研究所

项目金额： 86万元

中文摘要： 针对目前抗深部真菌感染药物缺乏、副作用大、易产生耐药性等问题，同时鉴于申请者前期研究发现新结构类型化合物双吴茱萸碱（Er-1）具有显著抗真菌活性，本项目拟选择富含吲哚喹唑啉生物碱的吴茱萸属植物为研究对象，运用1H-NMR、UPLC/Q-TOF/MS技术导向分离，采用最低抑菌浓度、相对抑酶活性及与阳性药对照耐受性好为评价体系，高效快速地分离到新型吲哚喹唑啉类活性成分；利用药物辅助软件Discovery studio 3.1虚拟筛选，指导结构修饰，制备系列新吲哚喹唑啉衍生物；采用流式细胞仪、Roman光谱和GC-MS等测定方法从细胞和分子水平上研究吲哚喹唑啉生物碱及其衍生物对靶酶羊毛甾醇14α-去甲基化酶（CYP51）的抑酶活性，全面阐明吲哚喹唑啉生物碱抗真菌的构效关系；发现1-2个高效、安全的抗真菌先导化合物，为研制抗深部真菌感染创新药物提供理论依据，也为吴茱萸属植物的科学利用提供新用途。

中文关键词： 吴茱萸；双吲哚喹唑啉生物碱；抗真菌活性；构效关系；羊毛甾醇14α-去甲基化酶

英文摘要： The project aims at solving the lack of anti-deep fungal drugs, serious side-effect, drug-resistance and other problems in the clinical therapy. Applicant's prior studies on the constituents of E. rutaecarpa have found that the new structure type alkaloid dievodiamine (Er-1) has significant antifungal activity, then we select Evodia genus plants rich in indole quinazoline alkaloids as the research object, applying with the separation-oriented 1H-NMR and LC-MS technology and adopt the minimum inhibitory ccentration (MIC) constracting with positive control as an activity evaluation system in order to confirm a new structure type of bisindole quinazolinone alkaloids fastly and efficiently as the active ingredients representatively. Analysing the results of virtule design by the auxiliary software - drug discovery studio 3.1 help to our chemical modification so that we can prepara a series of new indole quinazoline alkaloid derivatives. In addition, we will try to explore the antifungal structure-activity relationships (SAR) of the indole quinazoline alkaloid and its derivatives, clarifying their inhibition enzyme activity on the Lanosterol 14α Demethylase (CYP51) from the cellular and molecular level research using of flow cytometry instrument, Roman spectrum and GC-MS ect. As expected, one or two highly effective, safe lead compounds will be found. Our project not only provide new idea about scientific utilization of evodia plants, but also make the theory basis in the research and development of anti- fungal infection innovative drugs.

英文关键词： Evodia rutaecarpa;bisindole quinazoline alkaloids;antifungal activity;structure-activity relationships;Lanosterol 14α Demethylase