具有血管内皮细胞生长因子受体-2酪氨酸激酶抑制作用的链霉菌次生代谢产物2754R的研究  

Study of the secondary metabolite 2754R produced by streptomyces as inhibitor of VEGFR2-CD

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：《中国医药生物技术》2014年第3期180-184,共5页Chinese Medicinal Biotechnology

基　　金：国家自然科学基金(81172963);"重大新药创制"国家科技重大专项(2012ZX09301-002-001-018);北京市自然科学基金(7133249);中国医学科学院医药生物技术研究所中央级公益性科研院所基本科研业务专项(IMBF201204)

摘　　要：目的分离鉴定链霉菌I06A-02754发酵液中具血管内皮生长因子受体-2酪氨酸激酶(VEGFR2-CD)抑制活性的强极性次生代谢产物。方法采用大孔吸附树脂、阴离子交换树脂、MPLC、HPLC等分离手段对次生代谢产物进行分离纯化;通过UV、IR、HR-ESI质谱、1D-NMR和2D-NMR对其结构进行鉴定,以ELISA法检测其次生代谢产物对VEGFR2-CD的抑制活性;以MTT法检测化合物对肿瘤细胞的抑制活性。结果从发酵液的水溶性部分分离得到一个极性较大的胡桃霉素类次生代谢产物——2754R;其化学结构与胡桃霉素D一致,对VEGFR2-CD表现出一定的抑制活性;MTT实验显示化合物2754R对HepG2细胞、MCF-7细胞和BEL-7402细胞没有明显的抑制活性(IC50>10μmol/L)。结论化合物2754R是具有VEGFR2-CD活性的胡桃霉素类次生代谢产物。Objective To discover antagonists of VEGFR2-CD from the fermentation broth produced by streptomyces strain I06A-02754. Methods Under guidance of ELISA assay against VEGFR2-CD, compound 2754R was isolated and purified by combination of different column chromatographies and HPLC. The structure of compound 2754R was identified by combination of analysis of UV, IR, HR-ESI-MS and 1D-NMR, 2D-NMR. The cytotoxicity of compound 2754R was tested by MTT assay. Results Compound 2754R was purified and structurally identified as Juglomycin group antibiotics, and was the same with Juglomycin D. Compound 2754R showed weak antagonistic activity against VEGFR2-CD by ELISA assay, but did not show obvious cytotoxicity on HepG2 （human hepatocellular carcinoma）, BEL-7402 （human hepatocellular carcinoma） and MCF-7 （human breast cancer） cell lines at 10μmol/L. Conclusion It is firstly reported compound 2754R （Juglomycin D） has antagonistic activity against VEGFR2-CD.

关 键 词：血管内皮生长因子受体2 链霉菌属 VASCULAR ENDOTHELIAL growth factor receptor-2 

分 类 号：R914[医药卫生—药物化学]