title: Design and synthesis of the stabilized analogs of belactosin A with the unnatural cis-cyclopropane structure.
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 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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Kawamura
authors.forename: Yuka
authors.initials: Y
authors.lastname: Unno
authors.forename: Akira
authors.initials: A
authors.lastname: Asai
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Arisawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shuto
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D003521:Cyclopropanes / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D045325:HCT116 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D003521:Cyclopropanes; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C406052:belactosin A; C030797:cyclopropane; D046988:Proteasome Endopeptidase Complex