Synthesis of the seco‐Limonoid BCD Ring System Identifies a Hsp90 Chaperon Machinery (p23) Inhibitor. Issue 6 (20th December 2018)

• Record Type: Journal Article
• Authors: Pinkerton, David M.; Chow, Sharon; Eisa, Nada H.; Kainth, Kashish; Vanden Berg, Timothy J.; Burns, Jed M.; Guddat, Luke W.; Savage, G. Paul; Chadli, Ahmed; Williams, Craig M.
• Is Part Of: Chemistry. Volume 25:Issue 6(2019)
• Page Start: 1451
• Page End: 1455
• Publication Date: 2018-12-20
• Subjects: BCD ring -- gedunin -- Hsp90p23 -- limonoids -- medicinal chemistry -- natural products; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201805420
• Languages: English
• ISSNs: 0947-6539

Abstract

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. Abstract : The first synthetic route to the BCD ring system of the seco ‐D‐ring limonoids has been devised. A synthetic intermediate displayed an equipotent p23 enzyme inhibitory effect to that of the more complex gedunin.