Advertisement

Synthetic Progress Towards a TMC-95 Analogue as a Potential Proteasome Inhibitor

  • M. Angels Estiarte
  • Amy M. Elder
  • Daniel H. Rich
Part of the American Peptide Symposia book series (APSY, volume 7)

Abstract

Recently, four novel compounds, TMC 95A-D 1 (R1, R2 = H or OH; R3, R4 = H, OH or CH3), have been isolated from the fermentation broth of Apiospora montagnei Sacc. TC 1093 [1,2], and shown to inhibit the 20S proteasome (IC50 = 5.4–60 nM), an eukaryotic threonine protease responsible for the degradation of most cell proteins [3]. Increased levels of this enzyme and subsequent protein breakdown have been related to different diseases such as malaria, inflammation and cancer. Thus, inhibition of the proteasome is currently becoming a promising therapeutic target. In this work, we describe the synthetic approaches towards the synthesis of a novel indole analog 2 of the core of 1 to evaluate its possible activity as a proteasome inhibitor (Figure 1).

Keywords

Fermentation Broth Proteasome Inhibitor Synthetic Approach Ring Size Indole Ring 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Wöjcik, C. Drug Discov. Today 4, 188 (1999).PubMedCrossRefGoogle Scholar
  2. 2. (a)
    Koguchi, Y., Kohno, J., Nisshio, M., Takahashi, K., Okuda, T., Komatsubara, S.J. J. Antibiot. 53, 105 (2000).PubMedCrossRefGoogle Scholar
  3. 2.(b)
    Kohno, J., Koguchi, Y., Nisshio, M., Nakao, K., Kuroda, M., Shimizu, R., Ohnuki, T., Komatsubara, S.J. J. Org. Chem. 65, 990 (2000).PubMedCrossRefGoogle Scholar
  4. 3. (a)
    Ma, D., Wu, Q. Tetrahedron Lett. 41, 9089 (2000).CrossRefGoogle Scholar
  5. 3.(b)
    Albrecht, B.K., Williams, R.M. Tetrahedron Lett. 42, 2755 (2001).CrossRefGoogle Scholar
  6. 3. (c)
    Lin, S., Danishefsky, S.J. Angew. Chem., Int. Ed. 40, 1967 (2001).CrossRefGoogle Scholar
  7. 4. (a)
    Elder, A.M., Rich, D.H. Org. Lett. 1, 1443 (1999).PubMedCrossRefGoogle Scholar
  8. 4. (b)
    Elder, A.M., Rich, D.H. Org. Lett. 2001, submitted.Google Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2001

Authors and Affiliations

  • M. Angels Estiarte
    • 1
  • Amy M. Elder
    • 1
  • Daniel H. Rich
    • 1
  1. 1.Department of ChemistryUniversity of Wisconsin-MadisonMadisonUSA

Personalised recommendations