4-amino derivatives of the Hsp90 inhibitor CCT018159
4-amino derivatives of the Hsp90 inhibitor CCT018159
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DOI：
10.1016/j.bmcl.2006.01.099
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发表时间：
2006-05-01
影响因子：
2.7
通讯作者：
Wright, L
中科院分区：
文献类型：
--
作者：
Barril, X;Beswick, MC;Wright, L
描述了基于吡唑的Hsp90抑制剂CCT018159的新型哌嗪、吗啉和哌啶衍生物。结合人Hsp90 N-末端结构域的新化合物的X-射线共晶分析已经阐明了结构-活性关系。结合模式的主要特征与最近报道的有效类似物VER-49009基本相同。新化合物中最有效的是在哌嗪氮上附加了甲磺酰基苯基，与酶结合的IC50小于600 nm，对肿瘤细胞增殖的抑制微摩尔数很低。(C)2006爱思唯尔有限公司。保留所有权利。
Novel piperazinyl, morpholino and piperidyl derivatives of the pyrazole-based Hsp90 inhibitor CCT018159 are described. Structure-activity relationships have been elucidated by X-ray co-crystal analysis of the new Compounds bound to the N-terminal domain of human Hsp90. Key features of the binding mode are essentially identical to the recently reported potent analogue VER-49009. The most potent of the new compounds has a methylsulfonylbenzyl substituent appended to the piperazine nitrogen, possesses an IC50 of less than 600 nM binding against the enzyme and demonstrates low micromolar inhibition of tumour cell proliferation. (C) 2006 Elsevier Ltd. All rights reserved.