链霉菌I06A-03304产生的二酮哌嗪类化合物的纯化及结构鉴定

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院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.