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Design and synthesis of the stabilized analogs of belactosin A with the unnatural cis-cyclopropane structure
| 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) |
| URI: | http://hdl.handle.net/2115/56729 |
| Appears in Collections: | 薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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Submitter: 周東 智
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