Development of Noviomimetics as C-Terminal Hsp90 Inhibitors

ACS Medicinal Chemistry Letters
Mercy AnyikaBrian S J Blagg

Abstract

KU-32 and KU-596 are novobiocin-derived, C-terminal heat shock protein 90 (Hsp90) modulators that induce Hsp70 levels and manifest neuroprotective activity. However, the synthetically complex noviose sugar requires 10 steps to prepare, which makes translational development difficult. In this study, we developed a series of "noviomimetic" analogues of KU-596, which contain noviose surrogates that can be easily prepared, while maintaining the ability to induce Hsp70 levels. Both sugar and sugar analogues were designed, synthesized, and evaluated in a luciferase reporter assay, which identified compound 37, a benzyl containing noviomimetic, as the most potent inducer of Hsp70.

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Citations

Apr 21, 2018·Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry·Sonja SchmidThorsten Hugel
Sep 15, 2018·The Journal of Biological Chemistry·Jason E Gestwicki, Hao Shao
Jul 29, 2016·Proceedings of the National Academy of Sciences of the United States of America·Kendrick H YimLeonard Neckers
Jun 20, 2016·Current Diabetes Reports·Rick T Dobrowsky
Sep 15, 2019·Bioorganic & Medicinal Chemistry·David Bickel, Holger Gohlke
May 16, 2018·Bioorganic & Medicinal Chemistry Letters·Zheng ZhangBrian S J Blagg

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