发现二取代硼烷作为热休克蛋白 90 和热休克因子 1 相互作用的抑制剂

IF 4 3区 医学 Q2 CHEMISTRY, MEDICINAL
Yujie Shao, Kazuki Miura, Yasunobu Asawa, Taiki Morita, Guangzhe Li and Hiroyuki Nakamura*, 
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引用次数: 0

摘要

高效合成了二取代对位硼烷和正位硼烷(分别为 2 和 3)。在合成的化合物中,3e 通过基于细胞的报告基因检测,显示出在缺氧条件下对缺氧诱导因子 1(HIF-1)转录活性的强效抑制作用。详细的作用机制研究显示,3e 通过抑制 HSP90 合子的活性,降低了 CDK4、AKT 和细胞周期蛋白 D1 等热休克蛋白(HSP)90 客户蛋白的稳定性,但并没有诱导可能导致耐药性的热休克反应(HSR)。此外,3e 还能抑制 HSP90 与热休克因子 1(HSF1)之间的相互作用,从而降低 HSF1 蛋白的稳定性,进而抑制热休克蛋白的转录。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Discovery of Disubstituted Carboranes as Inhibitors of Heat Shock Protein 90–Heat Shock Factor 1 Interaction

Discovery of Disubstituted Carboranes as Inhibitors of Heat Shock Protein 90–Heat Shock Factor 1 Interaction

Discovery of Disubstituted Carboranes as Inhibitors of Heat Shock Protein 90–Heat Shock Factor 1 Interaction

Efficient synthesis of disubstituted para- and ortho-carboranes (2 and 3, respectively) was achieved. Among the compounds synthesized, 3e showed potent suppression of hypoxia-inducible factor 1 (HIF-1) transcriptional activity under hypoxia by a cell-based reporter gene assay. Detailed mechanism-of-action studies revealed that 3e reduced the stability of heat shock protein (HSP) 90 client proteins such as CDK4, AKT, and cyclin D1 by inhibiting HSP90 chaperone activity but did not induce a heat shock response (HSR), which may cause drug resistance. Furthermore, 3e inhibited the interaction between HSP90 and heat shock factor 1 (HSF1), resulting in reducing HSF1 protein stability and thereby suppressing the transcription of heat shock proteins.

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来源期刊
ACS Medicinal Chemistry Letters
ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-
CiteScore
7.30
自引率
2.40%
发文量
328
审稿时长
1 months
期刊介绍: ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.
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