open access

https://hdl.handle.net/2115/56729

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

英語

2013-10-14

Royal soc chemistry

Organic & biomolecular chemistry

11(38)

6615-6622

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.

学術雑誌論文

Accepted Manuscript

1477-0520