由一株放线菌产生的对谷胱苷肽转移酶具有抑制作用的活性化合物的研究

Study on glutathione S-transferase inhibitory derived from an actinomycete

谷胱苷肽-S-转移酶-π(GST-π)的活性在某些类型的癌症患者中有显著的升高并且在癌症细胞对抗癌药物耐药性的形成过程中起着重要的作用。抑制过量表达的GST-π的酶活性将有助于克服肿瘤细胞的耐药性,因此,GST-π被认为是一个潜在的药物作用靶点。利用我所建立的GST-π抑制剂高通量筛选模型,在筛选针对GST-π的新的抗癌药物增敏剂的过程中,发现由一株放线菌550产生的发酵代谢产物对来源于人的GST-π产生明显的抑制活性。经有机溶媒萃取、葡聚糖凝胶LH-20柱层析、HPLC制备等方法,从该菌的发酵液中分离到了一个对GST-π有中等程度抑制活性的化合物550-a,其IC50为21.4μg/ml,经各种理化性质及NMR分析确定该化合物与木黄酮(genistein)同质,该化合物对GST-π的酶抑制活性以前尚未见报道。

ABSTRACT Glutathione S-transferase-π （GST-π） level usually increased apparently in sufferring from certain kinds of cancers, and it played an important role in the process of drug resistant tumor cells against anti-tumor agents. Inhibition of the overexpressed enzyme activity will contribute to overcome the resistance. Therefore, GST-π has been considered as a potential drug target for the cancer treatment. By using the GST-π high throughput screening system model which was developed in our laboratory, an actinomycete strain No. 550 has shown inhibitory activity to GST-π. A compound named No. 550-A was isolated from the mycelium, and by solvent＇ extraction by Sephadex LH-20 column chromatography, and HPLC purification, the compound showed moderate activity against GST-π with the IC50 of 21.4μg/ml, by physico-chemical spectral analysis, the structure of the compound was identical with genistein, of which having inhibitory activity against GST-π was firstly reported.