BACKGROUND DNA topoisomerases are a class of enzymes that play a critical role in fundamental biological processes of replication, transcription, recombination, repair and chromatin remodeling. Amsacrine (m-AMSA), the best-known compound of 9-anilinoacridines series, was one of the first DNA-intercalating agents to be considered a Topoisomerase II inhibitor. OBJECTIVES A series of sulfur-containing 9-anilinoacridines related to amsacrine were synthesized and evaluated for their anticancer activity. METHODS Cell viability was assessed by the MTT assay. The topoisomerase II inhibitory assay was performed using the Human topoisomerase II Assay kit, and flow cytometry was used to evaluate the effects on the cell cycle of K562 cells. Molecular docking was performed using the Schrödinger Maestro program. RESULTS Compound 36 was found to be the most cytotoxic of the sulfide series against SW620, K562, and MCF-7. The limited SAR suggested the importance of the methansulfonamidoacetamide side chain functionality, the lipophilicity, and the relative metabolic stability of 36 in contributing to the cytotoxicity. Topoisomerase II α inhibitory activity appeared to be involved in the cytotoxicity of 36 through the inhibition of decatenation of kinetoplast DNA (kDNA) in a concentration- dependent manner. Cell cycle analysis further showed Topo II inhibition through the accumulation of K562 cells in the G2/M phase of the cell cycle. The docking of 36 into the Topo II α-DNA complex suggested that it may be an allosteric inhibitor of Topo II α. CONCLUSION Compound 36 exhibits anticancer activity by inhibiting topoisomerase II, and it could further be evaluated in in vivo models.

中文翻译：

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含硫 9-苯胺吖啶的合成及抗癌评价。

背景技术DNA拓扑异构酶是一类在复制、转录、重组、修复和染色质重塑的基本生物学过程中起关键作用的酶。安吖啶 (m-AMSA) 是 9-苯胺吖啶系列中最著名的化合物，是最早被认为是拓扑异构酶 II 抑制剂的 DNA 嵌入剂之一。目的合成一系列与安吖啶相关的含硫9-苯胺吖啶并评价其抗癌活性。方法 细胞活力通过 MTT 法进行评估。使用人拓扑异构酶II检测试剂盒进行拓扑异构酶II抑制测定，流式细胞仪用于评估对K562细胞细胞周期的影响。使用薛定谔大师程序进行分子对接。结果发现化合物 36 是硫化物系列中对 SW620、K562 和 MCF-7 最具细胞毒性的。有限的 SAR 表明甲磺酰胺基乙酰胺侧链功能性、亲脂性和 36 的相对代谢稳定性在促进细胞毒性方面的重要性。拓扑异构酶 II α 抑制活性似乎与 36 的细胞毒性有关，通过以浓度依赖性方式抑制运动质体 DNA (kDNA) 的决定。细胞周期分析进一步显示通过在细胞周期的 G2/M 期积累 K562 细胞来抑制 Topo II。36 与 Topo II α-DNA 复合物的对接表明它可能是 Topo II α 的变构抑制剂。结论 化合物 36 通过抑制拓扑异构酶 II 表现出抗癌活性，