Inhibition of Hsp90 with synthesis macrolactones: Synthesis and structural and biological evaluation of ring and conformational analogs of radicicol
Inhibition of Hsp90 with synthesis macrolactones: Synthesis and structural and biological evaluation of ring and conformational analogs of radicicol
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DOI：
10.1016/j.chembiol.2006.09.015
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发表时间：
2006-11-01
影响因子：
--
通讯作者：
Moody, Christopher J.
中科院分区：
文献类型：
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作者：
Proisy, Nicolas;Sharp, Swee Y.;Moody, Christopher J.
用化学合成法合成了一系列环大小和构象不同的苯并大内酯类化合物，并用结构和生物技术进行了表征。因此，以关环复分解为关键步骤，通过简明的路线得到了12-16元内酯。在酶分析中，13元、15元和16元类似物是很好的抑制剂，表明它们可以采用所需的构象来适应ATP结合部位。13-、14-和15-成员内酯与酵母Hsp90的N-末端结构域共结晶证实了这一点，表明它们与“天然”的14-成员自由基醇结合类似。ATPase分析中最活跃的化合物也显示出对HCT116人结肠癌细胞的最大生长抑制效力，并显示出Hsp90抑制的分子特征，即客户蛋白的耗尽和Hsp70的上调。
A series of benzo-macrolactones of varying ring size and conformation has been prepared by chemical synthesis and evaluated by structural and biological techniques. Thus, 12- to 16-membered lactones were obtained by concise routes, involving ring-closing metathesis as a key step. In enzyme assays, the 13-, 15-, and 16-membered analogs are good inhibitors, suggesting that they can adoptthe required conformation to fit in the ATP-binding site. This was confirmed by cocrystallization of 13-, 14-, and 15-membered lactones with the N-terminal domain of yeast Hsp90, showing that they bind similarly to the "natural" 14-membered radicicol. The most active compounds in the ATPase assays also showed the greatest growth-inhibitory potency in HCT116 human colon cancer cells and the established molecular signature of Hsp90 inhibition, i.e., depletion of client proteins with upregulation of Hsp70.