Synthesis of Lithocholic Acid Derivatives as Proteasome Regulators

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• 作者：Zhao Dang ; Kathy Jung ; Keduo Qian ; Kuo-Hsiung Lee ; Li Huang ; Chin-Ho Chen
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：November 8, 2012
• 年：2012
• 卷：3
• 期：11
• 页码：925-930
• 全文大小：302K
• 年卷期：v.3,no.11(November 8, 2012)
• ISSN：1948-5875

文摘

Accumulation of aberrant protein aggregates, such as amyloid 尾 peptide (A尾), due to decreased proteasome activities, might contribute to the neurodegeneration in Alzheimer's disease. In this study, lithocholic acid derivatives 3伪-O-pimeloyl-lithocholic acid methyl ester (2) and its isosteric isomer (6) were found to activate the chymotrypsin-like activity of the proteasome at an EC₅₀ of 7.8 and 4.3 渭M, respectively. Replacing the C24 methyl ester in 2 with methylamide resulted in a complete devoid of proteasome activating activity. Epimerizing the C3 substituent from an 伪 to 尾 orientation transformed the activator into a proteasome inhibitor. Unlike the cellular proteasome activator PA28, proteasome activated by 2 was not inhibited by A尾. Furthermore, 2 potently antagonized the inhibitory effect of A尾 on the proteasome. In summary, compound 2 represents a novel class of small molecules that not only activates the proteasome but also antagonizes the inhibitory effect of A尾 on the proteasome.

Keywords:

proteasome activator; lithocholic acid; Alzheimer's disease; amyloid 尾