Novobiocin: Redesigning a DNA gyrase inhibitor for selective inhibition of Hsp90
Novobiocin: Redesigning a DNA gyrase inhibitor for selective inhibition of Hsp90
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DOI：
10.1021/ja065793p
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发表时间：
2006-12-06
影响因子：
15
通讯作者：
Blagg, Brian S. J.
中科院分区：
文献类型：
--
作者：
Burlison, Joseph A.;Neckers, Len;Blagg, Brian S. J.
新生霉素是香豆霉素抗生素家族的成员，是一种公认的DNA回旋酶抑制剂。最近的研究表明，新生霉素结合到一个以前未认识的ATP结合位点的C-末端的热休克蛋白90和诱导降解热休克蛋白90依赖性客户蛋白在类似于700 μ M。为了开发更有效的C-末端结合位点抑制剂，制备新生霉素类似物的文库，并揭示初始结构-活性关系。这些数据表明香豆素环的4-羟基部分和Noviose附件的3 '-氨基甲酸酯对Hsp 90抑制活性是有害的。为了证实这些发现，制备了4-脱羟基新生霉素（DHN 1）和3 ′-脱氨基甲酰基-4-脱羟基新生霉素（DHN 2），并针对Hsp 90进行了评价。这两种化合物都明显比天然产物更有效，DHN 2被证明比DHN 1更有效。为了确定这些部分对DNA促旋酶抑制是否重要，测试了这些化合物抑制DNA促旋酶的能力，发现其表现出促旋酶活性的显著降低。因此，我们已经建立了第一组化合物，明确区分热休克蛋白90和DNA促旋酶的C-末端，转换成一个选择性的热休克蛋白90抑制剂，并确认了基本的构效关系香豆霉素家族的抗生素。
Novobiocin is a member of the coumermycin family of antibiotics and is a well-established inhibitor of DNA gyrase. Recent studies have shown that novobiocin binds to a previously unrecognized ATP-binding site at the C-terminus of Hsp90 and induces degradation of Hsp90-dependent client proteins at similar to 700 mu M. In an effort to develop more efficacious inhibitors of the C-terminal binding site, a library of novobiocin analogues was prepared and initial structure-activity relationships revealed. These data suggested that the 4-hydroxy moiety of the coumarin ring and the 3'-carbamate of the noviose appendage were detrimental to Hsp90 inhibitory activity. In an effort to confirm these findings, 4-deshydroxy novobiocin (DHN1) and 3'-descarbamoyl-4-deshydroxynovobiocin (DHN2) were prepared and evaluated against Hsp90. Both compounds were significantly more potent than the natural product, and DHN2 proved to be more active than DHN1. In an effort to determine whether these moieties are important for DNA gyrase inhibition, these compounds were tested for their ability to inhibit DNA gyrase and found to exhibit significant reduction in gyrase activity. Thus, we have established the first set of compounds that clearly differentiate between the C-terminus of Hsp90 and DNA gyrase, converted a well-established gyrase inhibitor into a selective Hsp90 inhibitor, and confirmed essential structure-activity relationships for the coumermycin family of antibiotics.