Forsberg Leah K, Anyika Mercy, You Zhenyuan, Emery Sean, McMullen Mason, Dobrowsky Rick T, Blagg Brian S J
Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, Malott 4070, The University of Kansas, Lawrence, KS 66045-7563, United States.
Department of Pharmacology and Toxicology Department, The University of Kansas, Lawrence, KS 66045, United States.
Eur J Med Chem. 2018 Jan 1;143:1428-1435. doi: 10.1016/j.ejmech.2017.10.038. Epub 2017 Oct 18.
Heat shock protein 90 (Hsp90) is a chaperone under investigation for the treatment of cancer and neurodegenerative diseases. Neuroprotective Hsp90 C-terminal inhibitors derived from novobiocin (novologues) include KU-32 and KU-596. These novologues modulate molecular chaperones and result in an induction of Heat Shock Protein 70 (Hsp70). "Noviomimetics" replace the synthetically complex noviose sugar with a simple cyclohexyl moiety to maintain biological efficacy as compared to novologues KU-596 and KU-32. In this study, we further explore the development of noviomimetics and evaluate their efficacy using a luciferase refolding assay, immunoblot analysis, a c-jun assay, and an assay measuring mitochondrial bioenergetics. These new noviomimetics were designed and synthesized and found to induce Hsp70 and improve biological activity. Noviomimetics 39e and 40a were found to induce Hsp70 and exhibit promising effects in cellular assays.
热休克蛋白90（Hsp90）是一种正在研究用于治疗癌症和神经退行性疾病的伴侣蛋白。源自新生霉素的具有神经保护作用的Hsp90 C末端抑制剂（类似物）包括KU-32和KU-596。这些类似物调节分子伴侣并导致热休克蛋白70（Hsp70）的诱导。与类似物KU-596和KU-32相比，“新霉素模拟物”用简单的环己基部分取代了合成复杂的新霉糖，以维持生物活性。在本研究中，我们进一步探索了新霉素模拟物的开发，并使用荧光素酶重折叠试验、免疫印迹分析、c-jun试验和测量线粒体生物能量学的试验来评估它们的功效。这些新的新霉素模拟物经过设计和合成，发现可诱导Hsp70并提高生物活性。发现新霉素模拟物39e和40a可诱导Hsp70并在细胞试验中显示出有前景的效果。
