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TMC-95A analogues with endocyclic biphenyl ether group as proteasome inhibitors
Authors:Kaiser Markus  Milbradt Alexander G  Siciliano Carlo  Assfalg-Machleidt Irmgard  Machleidt Werner  Groll Michael  Renner Christian  Moroder Luis
Affiliation:Max-Planck-Institut für Biochemie, AG Bioorganische Chemie, Am Klopferspilz 18A, D-82152 Martinsried.
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.
Keywords:
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