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Ring Expansion Leads to a More Potent Analogue of Ipomoeassin F

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posted on 02.12.2020, 18:37 by Guanghui Zong, Zhijian Hu, Kwabena Baffour Duah, Lauren E. Andrews, Jianhong Zhou, Sarah O’Keefe, Lucas Whisenhunt, Joong Sup Shim, Yuchun Du, Stephen High, Wei Q. Shi
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 Sec61α (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: ∼3 mg/kg).