Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and The Purdue Center for Cancer Research, Purdue University , West Lafayette, Indiana 47907, United States.
J Med Chem. 2014 Feb 27;57(4):1289-98. doi: 10.1021/jm401471v. Epub 2014 Feb 6.
Optimization of the lactam ω-aminoalkyl substituents in a series of 7-azaindenoisoquinolines resulted in new anticancer agents with improved Top1 inhibitory potencies and cancer cell cytotoxicities. The new compounds 14-17 and 19 exhibited mean graph midpoint cytotoxicity (GI50) values of 21-71 nM in the NCI panel of 60 human cancer cell cultures. Ternary 7-azaindenoisoquinoline-DNA-Top1 cleavage complexes that persist for up to 6 h were detected in HCT116 colon cancer cells. Ternary complexes containing 7-azaindenoisoquinolines were significantly more stable than those in which camptothecin was incorporated. DNA content distribution histograms showed S-phase block 3 h after drug removal. Drug-induced DNA damage in HCT116 cells was revealed by induction of the histone γ-H2AX marker. The 7-azaindenoisoquinolines were able to partially overcome resistance in several drug-resistant cell lines, and they were not substrates for the ABCB1 drug efflux transporter. Molecular modeling studies indicate that the 7-azaindenoisoquinolines intercalate at the DNA cleavage site in DNA-Top1 covalent complexes with the lactam side chain projecting into the major groove. Overall, the results indicate that the 7-azaindenoisoquinolines are promising anticancer agents that merit further development.
优化一系列 7-氮杂吲哚并异喹啉中的内酰胺 ω-氨基烷基取代基，得到了具有改进的 Top1 抑制活性和癌细胞细胞毒性的新型抗癌剂。新化合物 14-17 和 19 在 NCI panel 的 60 个人类癌细胞培养物中表现出 21-71 nM 的平均图形中点细胞毒性（GI50）值。在 HCT116 结肠癌细胞中检测到持续长达 6 小时的三元 7-氮杂吲哚并异喹啉-DNA-Top1 断裂复合物。含有 7-氮杂吲哚并异喹啉的三元复合物比包含喜树碱的三元复合物稳定得多。DNA 含量分布直方图显示药物去除后 3 小时出现 S 期阻滞。在 HCT116 细胞中，药物诱导的 DNA 损伤通过诱导组蛋白 γ-H2AX 标记物来揭示。7-氮杂吲哚并异喹啉能够部分克服几种耐药细胞系中的耐药性，并且它们不是 ABCB1 药物外排转运蛋白的底物。分子建模研究表明，7-氮杂吲哚并异喹啉在内酰胺侧链 projecting 进入大沟的情况下，在 DNA-Top1 共价复合物中在 DNA 切割部位插入。总体而言，结果表明 7-氮杂吲哚并异喹啉是有前途的抗癌剂，值得进一步开发。
