1447826-05-2Relevant articles and documents
Design and synthesis of the stabilized analogs of belactosin A with the unnatural cis-cyclopropane structure
Kawamura, Shuhei,Unno, Yuka,Asai, Akira,Arisawa, Mitsuhiro,Shuto, Satoshi
, p. 6615 - 6622 (2013)
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 β-lactone moiety. Thus, to increase the stability of 2a by chemical modification, its analogs with a sterically more hindered β-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 β-lactone carbonyl moiety and the conformational flexibility of the molecule.
Investigation of the noncovalent binding mode of covalent proteasome inhibitors around the transition state by combined use of cyclopropylic strain-based conformational restriction and computational modeling
Kawamura, Shuhei,Unno, Yuka,Tanaka, Motohiro,Sasaki, Takuma,Yamano, Akihito,Hirokawa, Takatsugu,Kameda, Tomoshi,Asai, Akira,Arisawa, Mitsuhiro,Shuto, Satoshi
, p. 5829 - 5842 (2013/08/23)
To develop potent covalent inhibitors, the noncovalent interactions around the transition state to form covalent bonding should be optimized because the potency of the inhibitor can be depending on the energy of the transition state. Here, we report an efficient analysis of the noncovalent binding mode of a potent covalent proteasome inhibitor 3a around the transition state by a combined use of the chemical approach, i.e., the cyclopropylic strain-based conformational restriction, and the computational docking approach. Furthermore, we calculated the binding energy of a series of salinosporamide derivatives in the predicted noncovalent complex around the transition state with the simulation model of proteasome constructed in this study, which was well correlated to their pIC50. Thus, the proposed docking methods to predict the noncovalent binding mode around the transition state of covalent inhibitors will be helpful toward the development of covalent inhibitors.
