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Discovery of Novel Celastrol Derivatives as Hsp90-Cdc37 Interaction Disruptors with Antitumor Activity.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-12-03 , DOI: 10.1021/acs.jmedchem.9b01290 Na Li 1 , Manyi Xu 1 , Bing Wang 1 , Zhixian Shi 1 , Zihao Zhao 1 , Yunqing Tang 1 , Xinyue Wang 1 , Jianbo Sun 1 , Li Chen 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-12-03 , DOI: 10.1021/acs.jmedchem.9b01290 Na Li 1 , Manyi Xu 1 , Bing Wang 1 , Zhixian Shi 1 , Zihao Zhao 1 , Yunqing Tang 1 , Xinyue Wang 1 , Jianbo Sun 1 , Li Chen 1
Affiliation
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To develop novel and efficient heat shock protein 90–cell division cycle 37 (Hsp90–Cdc37) interaction disruptors, several lipophilic fragments were introduced into celastrol (CEL) to synthesize 48 new CEL derivatives. Among all the target compounds, 41 was screened with superior antiproliferative activity on related cancer cells (IC50: 0.41–0.94 μM) and 41 could decrease the level of the Hsp90–Cdc37 complex in A549 cells. The capability to disrupt the Hsp90–Cdc37 interaction was stronger than that of CEL. Furthermore, pull-down assay, UV assay, and molecular docking analysis all showed that 41 might disrupt the interaction of the Hsp90–Cdc37 complex by preferentially binding to Cdc37 in cancer cells. Further studies showed that 41 could significantly regulate the levels of Hsp90–Cdc37 clients, thereby inducing the apoptosis of cancer cells. Together, 41 is a novel Hsp90–Cdc37 disruptor by binding to Cdc37 (hydrogen bond and/or covalent bond). Our results may provide reference for the discovery of effective Hsp90–Cdc37 disruptors.
中文翻译：
发现新型Celastrol衍生物作为具有抗肿瘤活性的Hsp90-Cdc37相互作用干扰物。
为了开发新型有效的热休克蛋白90-细胞分裂周期37（Hsp90-Cdc37）相互作用干扰物，将几种亲脂性片段引入了Celastrol（CEL）中，以合成48种新的CEL衍生物。在所有目标化合物中，有41种被筛选出对相关癌细胞具有优异的抗增殖活性（IC 50：0.41-0.94μM），而41种可能会降低A549细胞中Hsp90-Cdc37复合物的水平。破坏Hsp90-Cdc37相互作用的能力强于CEL。此外，下拉分析，紫外线分析和分子对接分析均显示41可能通过优先结合癌细胞中的Cdc37来破坏Hsp90-Cdc37复合物的相互作用。进一步的研究表明41可以显着调节Hsp90–Cdc37客户的水平，从而诱导癌细胞的凋亡。通过结合Cdc37（氢键和/或共价键），41是一个新颖的Hsp90–Cdc37破坏者。我们的结果可能为发现有效的Hsp90–Cdc37干扰物提供参考。
更新日期：2019-12-03
中文翻译：
发现新型Celastrol衍生物作为具有抗肿瘤活性的Hsp90-Cdc37相互作用干扰物。
为了开发新型有效的热休克蛋白90-细胞分裂周期37（Hsp90-Cdc37）相互作用干扰物，将几种亲脂性片段引入了Celastrol（CEL）中，以合成48种新的CEL衍生物。在所有目标化合物中，有41种被筛选出对相关癌细胞具有优异的抗增殖活性（IC 50：0.41-0.94μM），而41种可能会降低A549细胞中Hsp90-Cdc37复合物的水平。破坏Hsp90-Cdc37相互作用的能力强于CEL。此外，下拉分析，紫外线分析和分子对接分析均显示41可能通过优先结合癌细胞中的Cdc37来破坏Hsp90-Cdc37复合物的相互作用。进一步的研究表明41可以显着调节Hsp90–Cdc37客户的水平，从而诱导癌细胞的凋亡。通过结合Cdc37（氢键和/或共价键），41是一个新颖的Hsp90–Cdc37破坏者。我们的结果可能为发现有效的Hsp90–Cdc37干扰物提供参考。
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