title: Potent proteasome inhibitors derived from the unnatural cis-cyclopropane isomer of Belactosin A: synthesis, biological activity, and mode of action.
abstract: The natural product belactosin A (1) with a trans-cyclopropane structure is a useful prototype compound for developing potent proteasome (core particle, CP) inhibitors. To date, 1 and its analogues are the only CP ligands that bind to both the nonprimed S1 pocket as well as the primed substrate binding channel; however, these molecules harbor a high IC50 value of more than 1 μM. We have performed structure-activity relationship studies, thereby elucidating unnatural cis-cyclopropane derivatives of 1 that exhibit high potency to primarily block the chymotrypsin-like active site of the human constitutive (cCP) and immunoproteasome (iCP). The most active compound 3e reversibly inhibits cCP and iCP similarly with an IC50 of 5.7 nM. X-ray crystallographic analysis of the yeast proteasome in complex with 3e revealed that the ligand is accommodated predominantly into the primed substrate binding channel and covalently binds to the active site threonine residue via its β-lactone ring-opening.
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: Anja
authors.initials: A
authors.lastname: List
authors.forename: Akirai
authors.initials: A
authors.lastname: Mizuno
authors.forename: Motohiro
authors.initials: M
authors.lastname: Tanaka
authors.forename: Takuma
authors.initials: T
authors.lastname: Sasaki
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Arisawa
authors.forename: Akira
authors.initials: A
authors.lastname: Asai
authors.forename: Michael
authors.initials: M
authors.lastname: Groll
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shuto
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000737:chemistry*; D004355:Drug Stability; D045325:HCT116 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007536:Isomerism; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D014867:Water / Q000737:chemistry
chemical_list: D003521:Cyclopropanes; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D061988:Proteasome Inhibitors; C406052:belactosin A; D014867:Water; C030797:cyclopropane; D046988:Proteasome Endopeptidase Complex