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

摘要

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.%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。