Abstract：
Three chromomycin derivatives, chromomycins A3 (1, CA3), A5 (2, CA5), and monodeacetylchromomycin A3 (3, MDA-CA3), were identified from the soil-derived Streptomyces sp. CGMCC 26516. A reinvestigation of the structure of CA5 is reported, of which the absolute configuration was unambiguously determined for the first time to be identical with that of CA3 based on nuclear magnetic resonance (NMR) data analysis as well as NMR and electronic circular dichroism calculations. Compounds 1-3 showed potent cytotoxicity against the non-small-cell lung cancer (NSCLC) cells (A549, H460, H157-c-FLIP, and H157-LacZ) and down-regulated the protein expression of c-FLIP in A549 cells. The IC50 values of chromomycins in H157-c-FLIP were higher than that in H157-LacZ. Furthermore, si-c-FLIP promoted anti-proliferation effect of chromomycins in NSCLC cells. In nude mice xenograft model, 1 and 2 both showed more potent inhibition on the growth of H157-lacZ xenografts than that of H157-c-FLIP xenografts. These results verify that c-FLIP mediates the anticancer effects of chromomycins in NSCLC.
摘要：
三种色霉素衍生物，色霉素A3（1，CA3），A5(2,CA5),和单脱乙酰色霉素A3（3，MDA-CA3），从土壤衍生的链霉菌中鉴定出。CGMCC26516。报告了对CA5结构的重新研究，根据核磁共振（NMR）数据分析以及NMR和电子圆二色性计算，首次明确确定其绝对构型与CA3相同。化合物1-3对非小细胞肺癌（NSCLC）细胞（A549，H460，H157-c-FLIP，和H157-LacZ），并下调A549细胞中c-FLIP的蛋白表达。H157-c-FLIP中的色霉素的IC50值高于H157-LacZ。此外，si-c-FLIP对非小细胞肺癌细胞中的色霉素抗增殖作用。在裸鼠异种移植模型中，图1和2对H157-lacZ异种移植物的生长均显示出比H157-c-FLIP异种移植物更有效的抑制。这些结果验证了c-FLIP介导了在NSCLC中的色霉素的抗癌作用。
