Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, and the Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, USA.
J Med Chem. 2010 Mar 11;53(5):1979-89. doi: 10.1021/jm901649x.
On the basis of the superimposition of the crystal structures of norindenoisoquinoline 5 and topotecan (2) bound in the topoisomerase I-DNA covalent complex, as well as molecular docking and quantum chemical calculations, the substituted norindenoisoquinoline 14a was designed by transporting the 9-dimethylaminomethyl group of topotecan to the 10-position of the norindenoisoquinoline 5. The desired compound 14a was synthesized and found to possess topoisomerase I inhibitory activity that was slightly better than that of the starting compound 5. A focused set of 10-substitued norindenoisoquinoline analogues were then synthesized. The imidazole-substituted compound 14c was highly cytotoxic when evaluated in a series of human leukemia, ovarian, and breast cancer cells.
基于与拓扑异构酶 I-DNA 共价复合物结合的去甲异喹啉酮 5 和拓扑替康（2）的晶体结构叠加，以及分子对接和量子化学计算，通过将拓扑替康的 9-二甲氨基甲基基团转移到去甲异喹啉酮 5 的 10 位，设计了取代的去甲异喹啉酮 14a。合成了所需的化合物 14a，并发现其具有拓扑异构酶 I 抑制活性，略优于起始化合物 5。然后合成了一组 10 位取代的去甲异喹啉酮类似物。在一系列人白血病、卵巢和乳腺癌细胞中评估时，咪唑取代的化合物 14c 具有很高的细胞毒性。
