Drugs targeting human topoisomerase II (topoII) are used in clinical practice since decades. Nevertheless, there is an urgent need for new and safer topoII inhibitors due to the emergence of secondary malignancies and the appearance of resistance mechanisms upon treatment with topoII-targeted anticancer drugs. In the present investigation, we report the discovery of a new topoII inhibitor, whose design was based on the structure of the natural product trypthantrin, a natural alkaloidal compound containing a basic indoloquinazoline moiety. This new topoII inhibitor, here numbered compound 5, is found to inhibit topoII with an IC₅₀ of 26.6 ± 4.7 μM. Notably, compound 5 is more potent than the template compound trypthantrin, and even than the widely used topoII-targeted clinical drug etoposide. In addition, compound 5 also exhibits high water solubility, a promising antiproliferative activity on different tumor cell lines such as acute leukemia, colon, and breast cancer. In light of these results, compound 5 represents a promising lead for developing new topoII inhibitors as anti-cancer therapeutic agents.

几十年来，针对人类拓扑异构酶II（topoII）的药物一直在临床实践中使用。然而，由于继发性恶性肿瘤的出现以及以靶向topoII的抗癌药物治疗后出现的耐药机制，迫切需要新的和更安全的topoII抑制剂。在本研究中，我们报告了一种新的topoII抑制剂的发现，该抑制剂的设计基于天然产物胰蛋白p聚糖的结构，胰蛋白ant呤是一种含有碱性吲哚并喹唑啉部分的天然生物碱化合物。发现这种新的topoII抑制剂（此处编号为化合物5）以26.6± 4.7μM的IC ₅₀抑制topoII 。值得注意的是，化合物5它比模板化合物胰蛋白聚糖更有效，甚至比广泛使用的靶向topoII的临床药物依托泊苷更有效。另外，化合物5还显示出高水溶性，对不同的肿瘤细胞系例如急性白血病，结肠癌和乳腺癌有希望的抗增殖活性。根据这些结果，化合物5代表了开发新的topoII抑制剂作为抗癌治疗剂的有希望的先导。