title: TMC-95A analogues with endocyclic biphenyl ether group as proteasome inhibitors.
abstract: TMC-95A, a cyclic tripeptide metabolite of Apiospora montagnei, is a potent competitive inhibitor of proteasome. Based on the X-ray structure of its complex with yeast proteasome, the synthetically challenging structure of this natural product was simplified in a first generation of analogues by replacing the highly oxidized side-chain biaryl system with a phenyl-oxindole group. In the present study, the TMC-95 biaryl group was substituted with a biphenyl ether with retainment of significant proteasome inhibition. Because of the facile synthetic access of tripeptides containing in i, i+2 positions residues of the isodityrosine type, this new generation of TMC-95 analogues may represent promising lead structures for further optimization of affinity and selectivity of proteasome inhibitors.
authors.affiliation: Max-Planck-Institut für Biochemie, AG Bioorganische Chemie, Am Klopferspilz 18A, D-82152 Martinsried.
authors.forename: Markus
authors.initials: M
authors.lastname: Kaiser
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Milbradt
authors.forename: Carlo
authors.initials: C
authors.lastname: Siciliano
authors.forename: Irmgard
authors.initials: I
authors.lastname: Assfalg-Machleidt
authors.forename: Werner
authors.initials: W
authors.lastname: Machleidt
authors.forename: Michael
authors.initials: M
authors.lastname: Groll
authors.forename: Christian
authors.initials: C
authors.lastname: Renner
authors.forename: Luis
authors.initials: L
authors.lastname: Moroder
mesh_terms: D001713:Biphenyl Compounds / Q000737:chemistry*; D004986:Ether / Q000737:chemistry; D010456:Peptides, Cyclic / Q000737:chemistry*; D011480:Protease Inhibitors / Q000737:chemistry*; D061988:Proteasome Inhibitors
chemical_list: D001713:Biphenyl Compounds; D010456:Peptides, Cyclic; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; C408291:TMC-95A; D004986:Ether