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Ring Expansion Leads to a More Potent Analogue of Ipomoeassin F
Guanghui Zong1, Zhijian Hu2, Kwabena Baffour Duah3
1Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States.
Abstract:
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).
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