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Design and synthesis of the stabilized analogs of belactosin A with the unnatural cis-cyclopropane structure

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Title: Design and synthesis of the stabilized analogs of belactosin A with the unnatural cis-cyclopropane structure
Authors: Kawamura, Shuhei Browse this author
Unno, Yuka Browse this author
Asai, Akira Browse this author
Arisawa, Mitsuhiro Browse this author →KAKEN DB
Shuto, Satoshi Browse this author →KAKEN DB
Issue Date: 14-Oct-2013
Publisher: Royal soc chemistry
Journal Title: Organic & biomolecular chemistry
Volume: 11
Issue: 38
Start Page: 6615
End Page: 6622
Publisher DOI: 10.1039/c3ob41338a
PMID: 23986389
Abstract: The belactosin A analog 2a, having the unnatural cis-cyclopropane structure instead of the trans-cyclopropane structure in belactosin A, is a much more potent proteasome inhibitor than belactosin A. However, its cell growth inhibitory effect is rather lower than that expected from its remarkable proteasome inhibitory effect, probably due to its instability under cellular conditions. We hypothesized that the instability of 2a was due to chemical and enzymatic hydrolysis of the strained beta-lactone moiety. Thus, to increase the stability of 2a by chemical modification, its analogs with a sterically more hindered beta-lactone moiety and/or cyclopropylic strain-based conformational restriction were designed and synthesized, resulting in the identification of a stabilized analog 6a as a proteasome inhibitor with cell growth inhibitory effects. Our findings suggest that the chemical and biological stability of 2a is significantly affected by the steric hindrance around its beta-lactone carbonyl moiety and the conformational flexibility of the molecule.
Type: article (author version)
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 周東 智

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