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TMC‐95A Analogues with Endocyclic Biphenyl Ether Group as Proteasome Inhibitors
Author(s) -
Kaiser Markus,
Milbradt Alexander G.,
Siciliano Carlo,
AssfalgMachleidt Irmgard,
Machleidt Werner,
Groll Michael,
Renner Christian,
Moroder Luis
Publication year - 2004
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.200490008
Subject(s) - chemistry , tripeptide , proteasome , oxindole , biphenyl , stereochemistry , ether , side chain , natural product , selectivity , metabolite , yeast , biochemistry , organic chemistry , peptide , polymer , catalysis
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.