A series of four aromatic extended bisamidines (12-15) differing in the nature of their terminal basic side chains were synthesized and evaluated for cytotoxic activity in MCF-7 cultured breast cancer cells. The concentrations of 12, 13, 14, and 15 needed to inhibit [3H]thymidine incorporation into DNA by 50% (IC50) were found to be 63 microM, 85 microM, 77 microM, and 97 microM, respectively. To test whether cytotoxic properties were related to DNA-binding and topoisomerase action, the bisamidines 12-15 were evaluated in a cell-free system. Data from the ethidium displacement assay showed that bisamidines 12-15 have significant affinity for DNA and show moderate specificity for AT base pairs. In the topoisomerase II assay, the relaxation of DNA was inhibited with all four drugs and the extent of inhibition was directly proportional to the drug concentration. This suggests that DNA binding may be implicated in the cytotoxicity of these bisamidines, possibly by inhibiting interactions between topoisomerase II and their DNA targets.

中文翻译：

---

芳香族扩展双am：体外合成，拓扑异构酶抑制和抗癌细胞毒性。

合成了一系列四个在其末端基本侧链性质上不同的芳族延伸双am（12-15），并评估了在MCF-7培养的乳腺癌细胞中的细胞毒活性。发现抑制50％（IC50）的[3H]胸苷掺入DNA所需的浓度12、13、14和15分别为63 microM，85 microM，77 microM和97 microM。为了测试细胞毒性是否与DNA结合和拓扑异构酶作用相关，在无细胞系统中评估了双am 12-15。乙锭置换试验的数据表明，双am 12-15对DNA具有显着的亲和力，并对AT碱基对显示适中的特异性。在拓扑异构酶II分析中，DNA的松弛被所有四种药物抑制，抑制程度与药物浓度成正比。这表明DNA结合可能与这些双的细胞毒性有关，可能是通过抑制拓扑异构酶II与其DNA靶标之间的相互作用引起的。