Ring Expansion Leads to a More Potent Analogue of Ipomoeassin F

[Image: see text] Two new ring-size-varying analogues (2 and 3) of ipomoeassin F were synthesized and evaluated. Improved cytotoxicity (IC(50): from 1.8 nM) and in vitro protein translocation inhibition (IC(50): 35 nM) derived from ring expansion imply that the binding pocket of Sec61α (isoform 1) c...

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Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2020
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808706/
https://www.ncbi.nlm.nih.gov/pubmed/33264019
http://dx.doi.org/10.1021/acs.joc.0c01659
Descripción
Sumario:[Image: see text] Two new ring-size-varying analogues (2 and 3) of ipomoeassin F were synthesized and evaluated. Improved cytotoxicity (IC(50): from 1.8 nM) and in vitro protein translocation inhibition (IC(50): 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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