Kaiser, Markus; Milbradt, Alexander G.; Sicilianoa, Carlo; Assfalg-Machleidt, Irmgard; Machleidt, Werner; Groll, Michael; Renner, Christian; Moroder, Luis:

TMC-95A analogues with endocyclic biphenyl ether group as proteasome inhibitors.

In: Chemistry & biodiversity : CB ; an official journal of the Center for the Study of Biological Complexity, Jg. 1 (2004) ; Nr. 1, S. 161-173
ISSN: 1612-1872
Zeitschriftenaufsatz / Fach: Biologie
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.

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