真菌来源的蛋白酶体抑制剂F04W2166A的研究

F04W2166A,a proteasome innhibitor from fungal metabolites

目的通过蛋白酶体抑制剂筛选模型从微生物代谢产物中筛选出具有蛋白酶体抑制活性的化合物。方法对1株筛选得到的阳性真菌进行放大发酵,通过硅胶和Sephadex LH-20柱色谱等分离手段进行单体化合物分离。结合理化性质和质谱及核磁共振等数据的分析,确定其化学结构。测定化合物的蛋白酶体抑制活性以及抗肿瘤细胞增殖活性。结果从1株具有活性的轮枝孢霉菌F04W2166中得到活性化合物F04W2166A,并确定其结构与环缩酚酞类已知化合物Pullularin C相同。体外酶抑制活性说明该化合物对蛋白酶体有很强的抑制活性,其IC50为3.1μg/mL。进一步的抗肿瘤细胞增殖活性结果证明该化合物对人结肠癌细胞株HT-29和人乳腺癌细胞株MDA-MB-231的增殖均有很高的抑制活性,其IC50分别为28.3和271.6ng/mL。结论 F04W2166A是一个环缩酚酞类的蛋白酶体抑制剂,具有强的体外抗肿瘤细胞增殖活性。

Objective To discover proteasome compound was isolated and purified with silica gel and identified by MS and NMR data analysis. The inhibitory inhibitors from microbial motebolites. Methods Active Sephadex LH-20 column chromatography, its structure was activity against proteasome was assayed by fluorometry, and the anti-proliferatory activity was measured by MTT method. Results An active compound named F04W2166A was isolated from a fungal strain, Verticillium F04W2166, and it was identified as known cyclic depsipeptide compound Pullularin C. F04W2166A showed strong inhibitory activity against proteasome with an IC50 value of 3.1 gg/mL. The further anti-proliferation results showed that F04W2166A remarkably inhibited the proliferation of human colon cell line HT-29 and human breast cancer cell line MDA-MB-231 with IC50 values of 28.3 and 271.6ng/mL, respectively. Conclusion F04W2166A （Pullularin C） was determined as a new class ofproteasome inhibitor with significant antitumor activity in vitro.