Chu M, Truumees I, Rothofsky M L, Patel M G, Gentile F, Das P R, Puar M S, Lin S L
Schering-Plough Research Institute, Kenilworth, NJ 07033-0359, USA.
J Antibiot (Tokyo). 1995 Dec;48(12):1440-5. doi: 10.7164/antibiotics.48.1440.
Sch 52900 (1) and Sch 52901 (2), two new inhibitors of c-fos proto-oncogene induction, have been isolated from the fermentation of broth of the fungal culture (SCF-1168), Gliocladium sp. Along with compounds 1 and 2, a known compound verticillin A (3) was also obtained from the culture. Structure elucidation of 1 and 2, accomplished by analysis of spectral data in comparison with the data of 3, revealed both 1 and 2 were found to be closely related to the verticillin family of diketopiperazines. All three compounds prevented serum-stimulated transcription of the human c-fos promoter, using a fos/lac Z reporter gene assay, with IC50 values of 1.5, 18 and 0.5 microM of 1, 2 and 3, respectively. Northern analysis revealed the exposure of cells to compound 3 causes inhibition of both phorbol ester-induced c-fos induction of serum-induced JE induction in the absence of inhibiting RNA synthesis, as measured by [3H]uridine incorporation. There results suggest that this class of compounds exerts antitumor activity by blocking a signal transduction pathway that is common to and necessary for the induction of at least a subset of immediate early genes involved in cell proliferation.
从绿粘帚霉菌株（SCF - 1168）的发酵液中分离出了两种新的c - fos原癌基因诱导抑制剂，即Sch 52900（1）和Sch 52901（2）。除了化合物1和2外，还从该培养物中获得了一种已知化合物轮枝菌素A（3）。通过与化合物3的数据对比分析光谱数据对1和2进行结构解析，结果表明1和2均与二酮哌嗪类轮枝菌素家族密切相关。使用fos/lac Z报告基因检测法，所有这三种化合物都能抑制人c - fos启动子的血清刺激转录，化合物1、2和3的IC50值分别为1.5、18和0.5微摩尔。Northern分析显示，用[3H]尿苷掺入法测定，在不抑制RNA合成的情况下，细胞暴露于化合物3会导致佛波酯诱导的c - fos诱导以及血清诱导的JE诱导均受到抑制。这些结果表明，这类化合物通过阻断一种信号转导途径发挥抗肿瘤活性，该信号转导途径对于诱导至少一部分参与细胞增殖的即时早期基因是共同且必需的。
