工程抗生素抗癌：优化新生霉素骨架产生抗增殖剂。
Engineering an antibiotic to fight cancer: optimization of the novobiocin scaffold to produce anti-proliferative agents.
机构信息
Department of Medicinal Chemistry, The University of Kansas, Lawrence, KS 66045-7563, USA.
出版信息
J Med Chem. 2011 Jun 9;54(11):3839-53. doi: 10.1021/jm200148p. Epub 2011 May 9.
Abstract
Development of the DNA gyrase inhibitor, novobiocin, into a selective Hsp90 inhibitor was accomplished through structural modifications to the amide side chain, coumarin ring, and sugar moiety. These species exhibit ∼700-fold improved anti-proliferative activity versus the natural product as evaluated by cellular efficacies against breast, colon, prostate, lung, and other cancer cell lines. Utilization of structure-activity relationships established for three novobiocin synthons produced optimized scaffolds, which manifest midnanomolar activity against a panel of cancer cell lines and serve as lead compounds that manifest their activities through Hsp90 inhibition.
摘要
通过对酰胺侧链、香豆素环和糖部分的结构修饰，将 DNA 拓扑异构酶抑制剂新生霉素开发成选择性 Hsp90 抑制剂。这些化合物在细胞效价方面对乳腺癌、结肠癌、前列腺癌、肺癌和其他癌细胞系的增殖活性比天然产物提高了约 700 倍。利用为三种新生霉素合成子建立的构效关系，产生了优化的支架，这些支架对一系列癌细胞系表现出中纳摩尔的活性，并作为先导化合物，通过 Hsp90 抑制发挥其活性。
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