TMC-95A analogues with endocyclic biphenyl ether group as proteasome inhibitors.
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.
Kaiser
Markus
M
Max-Planck-Institut für Biochemie, AG Bioorganische Chemie, Am Klopferspilz 18A, D-82152 Martinsried.
Milbradt
Alexander G
AG
Siciliano
Carlo
C
Assfalg-Machleidt
Irmgard
I
Machleidt
Werner
W
Groll
Michael
M
Renner
Christian
C
Moroder
Luis
L
D001713:Biphenyl Compounds / Q000737:chemistry*; D004986:Ether / Q000737:chemistry; D010456:Peptides, Cyclic / Q000737:chemistry*; D011480:Protease Inhibitors / Q000737:chemistry*; D061988:Proteasome Inhibitors
D001713:Biphenyl Compounds; D010456:Peptides, Cyclic; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; C408291:TMC-95A; D004986:Ether