Synthesis of Lithocholic Acid Derivatives as Proteasome Regulators.

Published

Journal Article

Accumulation of aberrant protein aggregates, such as amyloid beta peptide (Aβ), due to decreased proteasome activities might contribute to the neurodegeneration in Alzheimer's disease. In this study, lithocholic acid derivatives 3α-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 EC(50) of 7.8 and 4.3 μM, 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 alpha to beta orientation transformed the activator into a proteasome inhibitor. Unlike the cellular proteasome activator PA28, proteasome activated by 2 was not inhibited by Aβ. Furthermore, 2 potently antagonized the inhibitory effect of Aβ 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 Aβ on the proteasome.

Full Text

Duke Authors

Cited Authors

  • Dang, Z; Jung, K; Qian, K; Lee, K-H; Huang, L; Chen, C-H

Published Date

  • 2012

Published In

Volume / Issue

  • 3 / 11

Start / End Page

  • 925 - 930

PubMed ID

  • 23330053

Pubmed Central ID

  • 23330053

International Standard Serial Number (ISSN)

  • 1948-5875

Digital Object Identifier (DOI)

  • 10.1021/ml3001962

Language

  • eng

Conference Location

  • United States