McDonald L A, Eldredge G S, Barrows L R, Ireland C M
Department of Medicinal Chemistry, University of Utah, Salt Lake City 84112.
J Med Chem. 1994 Oct 28;37(22):3819-27. doi: 10.1021/jm00048a017.
Several new pyridoacridine alkaloids, dehydrokuanoniamine B (1), shermilamine C (2), and cystodytin J (3), in addition to the known compounds cystodytin A (4), kuanoniamine D (5), shermilamine B (6), and eilatin (7), were isolated from a Fijian Cystodytes sp. ascidian. Their structures were determined by analyses of spectroscopic data. These compounds along with a previously reported pyridoacridine, diplamine (8), showed dose-dependent inhibition of proliferation in human colon tumor (HCT) cells in vitro. All compounds inhibited the topoisomerase (TOPO) II-mediated decatenation of kinetoplast DNA (kDNA) in a dose-dependent manner. The pyridoacridines' ability to inhibit TOPO II-mediated decatenation of kDNA correlated with their cytotoxic potencies and their ability to intercalate into calf thymus DNA. These results suggest that disruption of the function of TOPO II, subsequent to intercalation, is a probable mechanism by which pyridoacridines inhibit the proliferation of HCT cells. Incorporation studies show that pyridoacridines disrupt DNA and RNA synthesis with little effect on protein synthesis. It appears that DNA is the primary cellular target of the pyridoacridine alkaloids. These results are consistent with those for known DNA intercalators.
除了已知化合物胱抑素A（4）、库安胺D（5）、谢米胺B（6）和艾拉丁（7）外，还从一种斐济囊海鞘中分离出了几种新的吡啶吖啶生物碱，即脱氢库安胺B（1）、谢米胺C（2）和胱抑素J（3）。通过光谱数据分析确定了它们的结构。这些化合物与先前报道的吡啶吖啶双胺（8）一起，在体外对人结肠肿瘤（HCT）细胞的增殖表现出剂量依赖性抑制作用。所有化合物均以剂量依赖性方式抑制拓扑异构酶（TOPO）II介导的动质体DNA（kDNA）解连环作用。吡啶吖啶抑制TOPO II介导的kDNA解连环作用的能力与其细胞毒性效力以及它们插入小牛胸腺DNA的能力相关。这些结果表明，插入后TOPO II功能的破坏是吡啶吖啶抑制HCT细胞增殖的一种可能机制。掺入研究表明，吡啶吖啶会破坏DNA和RNA的合成，而对蛋白质合成影响很小。看来DNA是吡啶吖啶生物碱的主要细胞靶点。这些结果与已知DNA嵌入剂的结果一致。
