链霉菌I06A-03304产生的二酮哌嗪类化合物的纯化及结构鉴定  

Isolation, purification and structural identification of diketopiperazines produced by streptomyces strain I06A-03304

作　　者：蒋忠科[1] 张洋[1] 郭连宏[1] 姜蓉[1] 孙承航[1] 

机构地区：[1]中国医学科学院&北京协和医学院医药生物技术研究所,北京100050

出　　处：《中国医药导报》2014年第18期4-8,共5页China Medical Herald

基　　金：国家十二五"重大新药创制"科技重大专项(编号2012ZX09301-002-001-018);高等学校博士学科点专项科研基金新教师类项目(编号20131106120027);北京市自然科学基金资助项目(编号7133249)

摘　　要：目的分离鉴定链霉菌I06A-03304发酵液中具血管内皮细胞生长因子受体-2胞内酪氨酸激酶(VEGFR2-CD)抑制活性的次生代谢产物。方法采用大孔吸附树脂、羟丙基葡聚糖凝胶(Sephadex LH-20)、C-18反相色谱(ODS)、高压液相色谱(HPLC)等分离手段对次生代谢产物进行分离纯化;通过二级质谱(ESI+-MS2)、紫外光谱(UV)、红外光谱(IR)、核磁共振波谱(NMR)对其结构进行鉴定,以酶联免疫吸附试验(ELISA)法检测其次生代谢产物对VEGFR2-CD的抑制活性。结果分离得到两个二酮哌嗪类化合物:3304A和3304C;化合物3304A的化学结构与环(脯氨酸-亮氨酸)一致,化合物3304C的化学结构与环(脯氨酸-苯丙氨酸)一致,均对VEGFR2-CD表现出一定的抑制活性。结论化合物3304A和3304C是具有VEGFR2-CD抑制活性的二酮哌嗪类次生代谢产物,并为本研究首次报道。Objective To discover antagonists of VEGFR2-CD from the fermentation broth produced by streptomyces strain I06A-03304. Methods Under guidance of ELISA assay against VEGFR2-CD, compounds 3304A and 3304C were isolated and purified by HP-20 absorption resin, Sephadex LH-20 gel, ODS reversed-phase chromatography and semi-preparative HPLC. The structures of compounds 3304A and 3304C were identified by combination of analysis of UV, IR, ESI＊-MS2 and NMR, Results Compounds 3304A and 3304C were purified and structurally identified as dike- topiperazines, and were the same with cyclo-（Pro-Leu） and cyclo-（Pro-Phe） respectively. Compounds 3304A and 3304C showed weak antagonistic activity against VEGFR2-CD by ELISA assay. Conclusion For the first time, it is re- ported diketopiperazine compounds 3304A and 3304 C have antagonistic activity against VEGFR2-CD.

关 键 词：血管内皮细胞生长因子受体-2胞内酪氨酸激酶 链霉菌 二酮哌嗪 拮抗剂 

分 类 号：R96[医药卫生—药理学]