Synthesis of the seco-Limonoid BCD Ring System Identifies a Hsp90 Chaperon Machinery (p23) Inhibitor.
Publication/Presentation Date
1-28-2019
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.
Volume
25
Issue
6
First Page
1451
Last Page
1455
ISSN
1521-3765
Published In/Presented At
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 (Weinheim an der Bergstrasse, Germany), 25(6), 1451–1455. https://doi.org/10.1002/chem.201805420
Disciplines
Medicine and Health Sciences
PubMedID
30570197
Department(s)
Fellows and Residents
Document Type
Article