Cagir Ali, Jones Shannon H, Gao Rong, Eisenhauer Brian M, Hecht Sidney M
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22901, USA.
J Am Chem Soc. 2003 Nov 12;125(45):13628-9. doi: 10.1021/ja0368857.
Luotonin A is a pyrroloquinazolinoquinoline alkaloid isolated from the Chinese herbal medicinal plant Peganum nigellastrum. Although previously shown to exhibit cytotoxicity against the murine leukemia P-388 cell line, the mechanism of action of luotonin A is unknown. Presently, we demonstrate that luotonin A stabilizes the human DNA topoisomerase I-DNA covalent binary complex, affording the same pattern of cleavage as the structurally related topoisomerase I inhibitor camptothecin. Luotonin A also mediated topoisomerase I-dependent cytotoxicity toward Saccharyomyces cerevisiae lacking yeast topoisomerase I, but harboring a plasmid having the human topoisomerase I gene under the control of a galactose promoter. This finding identifies a putative biochemical locus for the cytotoxic action of luotonin A and has important implications for the mechanism of action of camptothecin and the design of camptothecin analogues.
路脱辛A是从中国草药植物骆驼蓬中分离出的一种吡咯并喹唑啉喹啉生物碱。尽管之前已显示出路脱辛A对小鼠白血病P - 388细胞系具有细胞毒性，但其作用机制尚不清楚。目前，我们证明路脱辛A可稳定人DNA拓扑异构酶I - DNA共价二元复合物，产生与结构相关的拓扑异构酶I抑制剂喜树碱相同的切割模式。路脱辛A还介导了对缺乏酵母拓扑异构酶I但含有在半乳糖启动子控制下具有人拓扑异构酶I基因的质粒的酿酒酵母的拓扑异构酶I依赖性细胞毒性。这一发现确定了路脱辛A细胞毒性作用的一个假定生化位点，对喜树碱的作用机制及喜树碱类似物的设计具有重要意义。
