Skip to main content
Journal cover image

Synthesis of Lithocholic Acid Derivatives as Proteasome Regulators.

Publication ,  Journal Article
Dang, Z; Jung, K; Qian, K; Lee, K-H; Huang, L; Chen, C-H
Published in: ACS Med Chem Lett
2012

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

ACS Med Chem Lett

DOI

ISSN

1948-5875

Publication Date

2012

Volume

3

Issue

11

Start / End Page

925 / 930

Location

United States

Related Subject Headings

  • 3405 Organic chemistry
  • 3404 Medicinal and biomolecular chemistry
  • 1115 Pharmacology and Pharmaceutical Sciences
  • 0305 Organic Chemistry
  • 0304 Medicinal and Biomolecular Chemistry
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Dang, Z., Jung, K., Qian, K., Lee, K.-H., Huang, L., & Chen, C.-H. (2012). Synthesis of Lithocholic Acid Derivatives as Proteasome Regulators. ACS Med Chem Lett, 3(11), 925–930. https://doi.org/10.1021/ml3001962
Dang, Zhao, Kathy Jung, Keduo Qian, Kuo-Hsiung Lee, Li Huang, and Chin-Ho Chen. “Synthesis of Lithocholic Acid Derivatives as Proteasome Regulators.ACS Med Chem Lett 3, no. 11 (2012): 925–30. https://doi.org/10.1021/ml3001962.
Dang Z, Jung K, Qian K, Lee K-H, Huang L, Chen C-H. Synthesis of Lithocholic Acid Derivatives as Proteasome Regulators. ACS Med Chem Lett. 2012;3(11):925–30.
Dang, Zhao, et al. “Synthesis of Lithocholic Acid Derivatives as Proteasome Regulators.ACS Med Chem Lett, vol. 3, no. 11, 2012, pp. 925–30. Pubmed, doi:10.1021/ml3001962.
Dang Z, Jung K, Qian K, Lee K-H, Huang L, Chen C-H. Synthesis of Lithocholic Acid Derivatives as Proteasome Regulators. ACS Med Chem Lett. 2012;3(11):925–930.
Journal cover image

Published In

ACS Med Chem Lett

DOI

ISSN

1948-5875

Publication Date

2012

Volume

3

Issue

11

Start / End Page

925 / 930

Location

United States

Related Subject Headings

  • 3405 Organic chemistry
  • 3404 Medicinal and biomolecular chemistry
  • 1115 Pharmacology and Pharmaceutical Sciences
  • 0305 Organic Chemistry
  • 0304 Medicinal and Biomolecular Chemistry