Ring Expansion Leads to a More Potent Analogue of Ipomoeassin F | Zendy

Guanghui Zong | Zendy; Zhijian Hu | Zendy; Kwabena B. Duah | Zendy; Lauren Andrews | Zendy; Jianhong Zhou | Zendy; Sarah O’Keefe | Zendy; Lucas Whisenhunt | Zendy; Joong Sup Shim | Zendy; Yuchun Du | Zendy; Stephen High | Zendy; Wei Shi | Zendy

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Ring Expansion Leads to a More Potent Analogue of Ipomoeassin F

Author(s) -

Guanghui Zong,

Zhijian Hu,

Kwabena B. Duah,

Lauren Andrews,

Jianhong Zhou,

Sarah O’Keefe,

Lucas Whisenhunt,

Joong Sup Shim,

Yuchun Du,

Stephen High,

Wei Shi

Publication year - 2020

Publication title -

the journal of organic chemistry

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 1.2

H-Index - 228

eISSN - 1520-6904

pISSN - 0022-3263

DOI - 10.1021/acs.joc.0c01659

Subject(s) - chemistry , ring (chemistry) , ic50 , in vivo , stereochemistry , gene isoform , cytotoxicity , in vitro , combinatorial chemistry , biochemistry , organic chemistry , gene , microbiology and biotechnology , biology

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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