Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Material Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Molecules. 2022 Aug 7;27(15):5029. doi: 10.3390/molecules27155029.
C4 variation of 4'--demethyl-epipodophyllotoxin (DMEP) is an effective approach to optimize the antitumor spectra of this compound class. Accordingly, two series of novel DMEP derivatives were synthesized, and as expected, the antitumor spectra of these derivatives varied with different C4 substituents. Notably, most compounds showed significant inhibition against the etoposide (2)-resistant KBvin cells. Four of the compounds (, , and ) induced protein-linked DNA break (PLDB) levels higher than those of GL-331 () and , and are assumed to be topoisomerase II (topo II) poisons more potent than and . Compound , a potent topo II poison highly effective against KBvin cells, was further evaluated with a panel of tumor cells and was most active against HepG2. This compound also exhibited apparent in vivo antitumor efficacy in hepatoma 22 (H22) mouse model. The results indicated that C4 derivation of DMEP is a feasible approach to identify potent topo II inhibitors with optimized antitumor profiles.
C4 位取代的 4′--去甲基表鬼臼毒素（DMEP）是优化该类化合物抗肿瘤谱的有效方法。因此，我们合成了两个系列的新型 DMEP 衍生物，与预期的一样，这些衍生物的抗肿瘤谱随 C4 取代基的不同而变化。值得注意的是，大多数化合物对依托泊苷（2）耐药的 KBvin 细胞具有显著的抑制作用。其中 4 个化合物（、、和）诱导的蛋白相关 DNA 断裂（PLDB）水平高于 GL-331（）和，它们被认为是比和更有效的拓扑异构酶 II（topo II）毒物。化合物，一种对 KBvin 细胞有强效的拓扑异构酶 II 毒物，在一系列肿瘤细胞中进一步进行了评估，对 HepG2 细胞最为有效。该化合物在肝癌 22（H22）小鼠模型中也表现出明显的体内抗肿瘤活性。结果表明，DMEP 的 C4 衍生化是一种可行的方法，可以识别出具有优化抗肿瘤谱的强效拓扑异构酶 II 抑制剂。
