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Ring Expansion Leads to a More Potent Analogue of Ipomoeassin F.

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 Sec61? (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).

SUBMITTER: Zong G

PROVIDER: S-EPMC7808706 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Ring Expansion Leads to a More Potent Analogue of Ipomoeassin F.

Zong Guanghui G Hu Zhijian Z Duah Kwabena Baffour KB Andrews Lauren E LE Zhou Jianhong J O'Keefe Sarah S Whisenhunt Lucas L Shim Joong Sup JS Du Yuchun Y High Stephen S Shi Wei Q WQ

The Journal of organic chemistry 20201202 24

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 u ...[more]

PMID: 33264019

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