Ring Expansion Leads to a More Potent Analogue of Ipomoeassin F

by Zong, Guanghui; Hu, Zhijian; Duah, Kwabena Baffour; Andrews, Lauren E.; Zhou, Jianhong; O'Keefe, Sarah; Whisenhunt, Lucas; Shim, Joong Sup; Du, Yuchun; High, Stephen; Shi, Wei Q.

Two new ring-size-varying analogues (2 and 3) of ipomoeassin F were synthesized and evaluated. Improved cytotoxicity (IC50: from 1.8 nM) and in vitro protein translocation inhibition (IC50: 35 nM) derived from ring expansion imply that the binding pocket of Sec61 alpha (isoform 1) can accommodate further structural modifications, likely in the fatty acid portion. Streamlined preparation of the key diol intermediate 5 enabled gram-scale production, allowing us to establish that ipomoeassin F is biologically active in vivo (MTD: similar to 3 mg/kg).

Journal
Journal of Organic Chemistry
Volume
85
Issue
24
Year
2020
Start Page
16226
ISBN/ISSN
1520-6904; 0022-3263
PMID
33264019
DOI
10.1021/acs.joc.0c01659