Camptothecin (CPT) selectively traps topoisomerase 1-DNA cleavable complexes (Top1cc) to promote anticancer activity. Here, we report the design and synthesis of a new class of neutral porphyrin derivative 5,10-bis(4-carboxyphenyl)-15, 20-bis(4-dimethylaminophenyl)porphyrin (compound 8) as a potent catalytic inhibitor of human Top1. In contrast to CPT, compound 8 reversibly binds with the free enzyme and inhibits the formation of Top1cc and promotes reversal of the preformed Top1cc with CPT. Compound 8 induced inhibition of Top1cc formation in live cells was substantiated by fluorescence recovery after photobleaching (FRAP) assays. We established that MCF7 cells treated with compound 8 trigger proteasome-mediated Top1 degradation, accumulate higher levels of reactive oxygen species (ROS), PARP1 cleavage, oxidative DNA fragmentation, and stimulate apoptotic cell death without stabilizing apoptotic Top1-DNA cleavage complexes. Finally, compound 8 shows anticancer activity by targeting cellular Top1 and preventing the enzyme from directly participating in the apoptotic process.

中文翻译：

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中性卟啉衍生物通过靶向细胞拓扑异构酶 I (Top1) 发挥抗癌活性，并在不稳定 Top1-DNA 切割复合物的情况下促进凋亡细胞死亡。

喜树碱 (CPT) 选择性捕获拓扑异构酶 1-DNA 可裂解复合物 (Top1cc) 以促进抗癌活性。在这里，我们报告了一种新型中性卟啉衍生物 5,10-双（4-羧基苯基）-15, 20-双（4-二甲氨基苯基）卟啉（化合物 8）作为人类 Top1 的有效催化抑制剂的设计和合成。 . 与 CPT 相比，化合物 8 可逆地与游离酶结合并抑制 Top1cc 的形成，并促进预先形成的 Top1cc 与 CPT 的逆转。化合物 8 诱导的活细胞中 Top1cc 形成的抑制通过光漂白 (FRAP) 测定后的荧光恢复得到证实。我们确定用化合物 8 处理的 MCF7 细胞触发蛋白酶体介导的 Top1 降解，积累更高水平的活性氧 (ROS)、PARP1 切割、氧化 DNA 片段化、并在不稳定凋亡 Top1-DNA 裂解复合物的情况下刺激凋亡细胞死亡。最后，化合物 8 通过靶向细胞 Top1 并阻止酶直接参与细胞凋亡过程而显示出抗癌活性。