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New Tripeptide‐Based Macrocyclic Calpain Inhibitors Formed by N ‐Alkylation of Histidine
Author(s) -
Chen Hongyuan,
Jiao Wanting,
Jones Matthew A.,
Coxon James M.,
Morton James D.,
Bickerstaffe Roy,
Pehere Ashok D.,
Zvarec Ondrej,
Abell Andrew D.
Publication year - 2012
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.201200320
Subject(s) - peptidomimetic , chemistry , tripeptide , imidazole , stereochemistry , aldehyde , histidine , alkylation , calpain , active site , docking (animal) , peptide , amino acid , enzyme , biochemistry , catalysis , medicine , nursing
Two new series of 15‐membered macrocyclic peptidomimetics, in which the P1 and P3 residues of the peptide backbone are linked by a bridge containing a 1,4‐disubstituted 1 H ‐imidazole, are reported. The structure with an aldehyde at the C‐terminus and the imidazole at P3, i.e. , 4c , shows significant inhibitory activity against calpain 2, with an IC 50 value of 238 n M . The macrocyclic aldehyde with the imidazole at the alternative P1 position, i.e. , 5c , is significantly less active. The relative activities are linked to the ability of the component macrocycles to mimic a β ‐strand geometry that is known to favor active‐site binding. This ability is defined by conformational searches and docking studies with calpain.