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. 2012 Feb 23;55(4):1682-97. doi: 10.1021/jm201512x. Epub 2012 Feb 13.
A comprehensive study of a series of azaindenoisoquinoline topoisomerase I (Top1) inhibitors is reported. The synthetic pathways have been developed to prepare 7-, 8-, 9-, and 10-azaindenoisoquinolines. The present study shows that 7-azaindenoisoquinolines possess the greatest Top1 inhibitory activity and cytotoxicity. Additionally, the introduction of a methoxy group into the D-ring of 7-azaindenoisoquinolines improved their biological activities, leading to new lead molecules for further development. A series of QM calculations were performed on the model "sandwich" complexes of azaindenoisoquinolines with flanking DNA base pairs from the Drug-Top1-DNA ternary complex. The results of these calculations demonstrate how changes in two forces contributing to the π-π stacking (dispersion and charge-transfer interactions) affect the binding of the drug to the Top1-DNA cleavage complex and thus modulate the drug's Top1 inhibitory activity.
本文报道了一系列吖啶并异喹啉拓扑异构酶 I（Top1）抑制剂的综合研究。已经开发了合成途径来制备 7-、8-、9-和 10-吖啶并异喹啉。本研究表明，7-吖啶并异喹啉具有最强的 Top1 抑制活性和细胞毒性。此外，在 7-吖啶并异喹啉的 D-环中引入甲氧基可提高其生物活性，为进一步开发提供了新的先导分子。对来自药物-Top1-DNA 三元复合物的侧翼 DNA 碱基对的吖啶并异喹啉模型“夹心”复合物进行了一系列 QM 计算。这些计算的结果表明，两种影响 π-π 堆积（色散和电荷转移相互作用）的力的变化如何影响药物与 Top1-DNA 切割复合物的结合，从而调节药物的 Top1 抑制活性。
