设计、合成并评价二苯并[c,h][1,6]萘啶类化合物作为拓扑异构酶 I 抑制剂和潜在的抗癌药物。
Design, synthesis, and evaluation of dibenzo[c,h][1,6]naphthyridines as topoisomerase I inhibitors and potential anticancer agents.
机构信息
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy, and The Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, USA.
出版信息
J Med Chem. 2010 Dec 23;53(24):8716-26. doi: 10.1021/jm101048k. Epub 2010 Nov 23.
Abstract
Indenoisoquinoline topoisomerase I (Top1) inhibitors are a novel class of anticancer agents. Modifications of the indenoisoquinoline A, B, and D rings have been extensively studied in order to optimize Top1 inhibitory activity and cytotoxicity. To improve understanding of the forces that stabilize drug-Top1-DNA ternary complexes, the five-membered cyclopentadienone C-ring of the indenoisoquinoline system was replaced by six-membered nitrogen heterocyclic rings, resulting in dibenzo[c,h][1,6]naphthyridines that were synthesized by a novel route and tested for Top1 inhibition. This resulted in several compounds that have unique DNA cleavage site selectivities and potent antitumor activities in a number of cancer cell lines.
摘要
吲哚并异喹啉拓扑异构酶 I（Top1）抑制剂是一类新型的抗癌药物。为了优化 Top1 抑制活性和细胞毒性，对吲哚并异喹啉 A、B 和 D 环进行了广泛的修饰研究。为了更好地理解稳定药物-Top1-DNA 三元复合物的力，将吲哚并异喹啉系统的五元环戊二烯酮 C 环用六元氮杂环取代，得到了通过新途径合成的苯并[c,h][1,6]萘啶，并对其进行了 Top1 抑制测试。这导致了一些具有独特 DNA 切割位点选择性和在多种癌细胞系中具有强大抗肿瘤活性的化合物。
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