Development of Noviomimetics as C-Terminal Hsp90 Inhibitors
Development of Noviomimetics as C-Terminal Hsp90 Inhibitors
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DOI：
10.1021/acsmedchemlett.5b00331
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发表时间：
2016-01-01
影响因子：
4.2
通讯作者：
Blager, Brian S. J.
中科院分区：
文献类型：
--
作者：
Anyika, Mercy;McMullen, Mason;Blager, Brian S. J.
KU-32和KU-596是新生物素衍生的C端热休克蛋白90 （Hsp90）调节剂，可诱导Hsp70水平并表现出神经保护活性。然而，合成复杂的新糖需要10个步骤来制备，这给转化开发带来了困难。在本研究中，我们开发了一系列KU-596的“noviomimetic”类似物，其中含有易于制备的noviose代物，同时保持了诱导Hsp70水平的能力。糖和糖类似物都被设计、合成，并在荧光素酶报告试验中进行了评估，结果发现化合物37是一种含苯基的模拟物，是最有效的Hsp70诱导剂。
KU-32 and KU-596 are novobiocin-derived, C terminal heat shock protein 90 (Hsp90) modulators that induce Hsp70 levels and manifest neuroprotective activity. However, the synthetically complex noviose sugar requires 10 steps to prepare, which makes translational development difficult. In this study, we developed a series of "noviomimetic" analogues of KU-596, which contain noviose surrogates that can be easily prepared, while maintaining the ability to induce Hsp70 levels. Both sugar and sugar analogues were designed, synthesized, and evaluated in a luciferase reporter assay, which identified compound 37, a benzyl containing noviomimetic, as the most potent inducer of Hsp70.