Synthesis of the seco-Limonoid BCD Ring System Identifies a Hsp90 Chaperon Machinery (p23) Inhibitor

David M. Pinkerton, Sharon Chow, Nada H. Eisa, Kashish Kainth, Timothy J. Vanden Berg, Jed M. Burns, Luke W. Guddat, G. Paul Savage, Ahmed Chadli, Craig M. Williams

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

D-Ring-seco-limonoids (tetranortriterpenoids), such as gedunin and xylogranin B display anti-cancer activity, acting via inhibition of Hsp90 and/or associated chaperon machinery (e.g., p23). Despite this, these natural products have received relatively little attention, both in terms of an enabling synthetic approach (which would allow access to derivatives), and as a consequence their structure–activity relationship (SAR). Disclosed herein is a generally applicable synthetic route to the BCD ring system of the seco-D-ring double bond containing limonoids. Furthermore, cell based assays revealed the first skeletal fragment that exhibited inhibition of the p23 enzyme at a level which was equipotent to that of gedunin, despite being much less structurally complex.

Original languageEnglish (US)
Pages (from-to)1451-1455
Number of pages5
JournalChemistry - A European Journal
Volume25
Issue number6
DOIs
StatePublished - Jan 28 2019

Keywords

  • BCD ring
  • Hsp90p23
  • gedunin
  • limonoids
  • medicinal chemistry
  • natural products

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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    Pinkerton, D. M., Chow, S., Eisa, N. H., Kainth, K., Vanden Berg, T. J., Burns, J. M., Guddat, L. W., Savage, G. P., Chadli, A., & Williams, C. M. (2019). Synthesis of the seco-Limonoid BCD Ring System Identifies a Hsp90 Chaperon Machinery (p23) Inhibitor. Chemistry - A European Journal, 25(6), 1451-1455. https://doi.org/10.1002/chem.201805420