设计、合成及具有化学预防潜力的吲哚异喹啉雷帕霉素类化合物的生物评价。
Design, synthesis, and biological evaluation of indenoisoquinoline rexinoids with chemopreventive potential.
机构信息
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, USA.
出版信息
J Med Chem. 2013 Mar 28;56(6):2581-605. doi: 10.1021/jm400026k. Epub 2013 Mar 8.
Abstract
Nuclear receptors, such as the retinoid X receptor (RXR), are proteins that regulate a myriad of cellular processes. Molecules that function as RXR agonists are of special interest for the prevention and control of carcinogenesis. The majority of these ligands possess an acidic moiety that is believed to be key for RXR activation. This communication presents the design, synthesis, and biological evaluation of both acidic and nonacidic indenoisoquinolines as new RXR ligands. In addition, a comprehensive structure-activity relationship study is presented that identifies the important features of the indenoisoquinoline rexinoids. The ease of modification of the indenoisoquinoline core and the lack of the necessity of a carboxyl group for activity make them an attractive and unusual family of RXR agonists. This work establishes a structural foundation for the design of new and novel rexinoid cancer chemopreventive agents.
摘要
核受体，如视黄酸 X 受体 (RXR)，是调节众多细胞过程的蛋白质。作为 RXR 激动剂的分子对于预防和控制癌症发生特别有意义。这些配体中的大多数都具有酸性部分，据信这对于 RXR 的激活很关键。本通讯介绍了酸性和非酸性茚并异喹啉作为新型 RXR 配体的设计、合成和生物学评价。此外，还提出了一个全面的构效关系研究，确定了茚并异喹啉雷昔诺素的重要特征。茚并异喹啉核心易于修饰，而且活性不需要羧基，这使它们成为一类有吸引力的、不寻常的 RXR 激动剂。这项工作为设计新型雷昔诺素癌症化学预防剂奠定了结构基础。
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