Expanding the Repertoire of Chemical Modulators for Heat Shock Protein 70 (Hsp70):New Probes for Neurodegenerative Disease.

[摘要] Heat shock protein 70 (Hsp70) is a molecular chaperone that plays pivotal roles in protein homeostasis in nearly all organisms. In these roles, Hsp70 binds to newly synthesized or misfolded proteins and regulates their stability and turnover. Genetic and biochemical data have strongly implicated Hsp70 in many diseases, including cancer and neurodegeneration. However, there are few Hsp70 inhibitors available. This limitation has prevented detailed studies of Hsp70’s roles in disease and has limited exploration of its potential as a drug target.The purpose of this study is to synthesize new chemical probes that could be used to aid in our understanding of Hsp70’s biology. Early Hsp70 inhibitors were assembled by the multi-component Biginelli reaction and they contained a dihydropyrimidine core. In my work, this reaction was further exploited to assemble a focused library of related compounds. This new series allowed for the identification of the putative binding site on Hsp70 and provided new insight into the relationship between Hsp70 and amyloid formation. Based on this work, I generated a series of related dihydropyridines through the four-component, Hantzsch reaction. During the course of that work, an enantioselective route was developed using an organophosphorous catalyst. Some of these compounds showed promising activity in cellular models of neurodegeneration. Finally, derivatives of the natural product analog, 15-deoxyspergualin, were synthesized through the strategic use of the Ugi multi-component reaction. We found that this route provided for the rapid and efficient generation of derivatives, with increased opportunities for structural diversity. These compounds appeared to interrupt binding of Hsp70 to its co-chaperone, CHIP, and they blocked protein aggregation in cellular models.Through utilizing different multi-component reactions, it has been possible to synthesize several new inhibitors of Hsp70. These probes have been used to better understand the relationships between Hsp70 and neurodegeneration. Thus, this series may aid in future efforts to understand Hsp70’s biology.

[发布机构] University of Michigan

[效力级别] Chemistry

[关键词] Developing Chemical Probes for Neurodegenerative Diseases Employing Multicomponent Reactions;Chemistry;Science;Chemical Biology