A series of thiochromeno[2,3-c]quinolin-12-one derivatives with various substitutions were synthesized and evaluated as topoisomerase (Topo) inhibitors. Six (8, 10, 12, 14, 19, and 26) of 23 compounds showed strong inhibitory activities against Topo-mediated DNA relaxation and proliferation of five human cell lines including breast (MDA-MB-231, MDA-MB-468 and MCF7), colorectal (HCT116) and non-small cell lung (H1299) cancers. Among these, compounds 14 and 26 exhibited full inhibitory activities against Topo I at 3 μM and Topo IIα at 1 μM. Cancer cells treated with 26 accumulated DNA damage and were arrested at the G2/M phase. With time, cells proceeded to apoptosis, as revealed by increased amounts of cells with fragmented DNA and cleavage of caspase-8 and -9. In contrast, normal breast epithelial cells showed low sensitivity to 26. Taken together, our study identifies 26 as a potent Topo dual-inhibitor with low toxicity to normal cells, and elucidates that the terminal amino group of N-2-aminoethylamino or N-3-aminopropylamino at the 6th position and 8,10-di-halogen substituents on thiochromeno[2,3-c]quinolin-12-one are critical for the Topo-inhibiting and cancer-killing activities.

中文翻译：

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设计，合成和生物学评估杂四环喹啉酮衍生物作为靶向拓扑异构酶的抗癌药。

合成了一系列具有各种取代基的硫代色素[2,3-c]喹啉-12-衍生物，并作为拓扑异构酶（Topo）抑制剂进行了评估。23种化合物中的6种（8、10、12、14、19和26）显示出对Topo介导的DNA松弛和包括乳腺在内的5种人类细胞系（MDA-MB-231，MDA-MB-468和MCF7），大肠癌（HCT116）和非小细胞肺癌（H1299）癌症。其中，化合物14和26对3μM的Topo I和1μM的TopoIIα表现出完全的抑制活性。经过26种处理的癌细胞累积了DNA损伤，被阻滞在G2 / M期。随着时间的流逝，细胞继续凋亡，这表现为DNA碎片化的细胞数量增加以及caspase-8和-9的裂解。相反，正常的乳腺上皮细胞对26的敏感性较低。