New Tripeptide‐Based Macrocyclic Calpain Inhibitors Formed by N‐Alkylation of Histidine

Abstract

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 1H-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 nM. 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.

Dynamic Docking of Conformationally Constrained Macrocycles: Methods and Applications

“…Subsequent efforts yielded a different compound bridged through a 1,4-disubsituted imidazole, exhibiting 76% β-strand character, which was 3fold more potent. 60 The authors speculate the difference in potency arises from energetically accessible inactive poses that allow the compound to access the active site.…”

“…Interestingly, though macrocyclic ligands with a 16-member macrocycle possessed nearly 100% β-strand character, the most potent compound in the series, CAT811, displayed only 8% β-strand character. Subsequent efforts yielded a different compound bridged through a 1,4-disubsituted imidazole, exhibiting 76% β-strand character, which was 3-fold more potent . The authors speculate the difference in potency arises from energetically accessible inactive poses that allow the compound to access the active site.…”

New 26S Proteasome Inhibitors with High Selectivity for Chymotrypsin-Like Activity and p53-Dependent Cytotoxicity

“…These azides also allow cyclization to the acetylene of P1 via Huisgen cycloaddition, in order to investigate the effect of constraining the backbone into a β-strand geometry (see compounds 3a and 4a ). This geometry is known to favor ligand binding to the proteasome and indeed all other proteases. − While inhibitors of the proteasome reportedly adopt hydrogen bonds with the protease that are characteristic of binding in this geometry, unlike other proteases, the P2 group does not seem to form important contacts with the active site . Presumably this accounts for the earlier discussed observation that the corresponding S2 pocket is not critical for binding to the CT-L subunit.…”

Design, synthesis, and applications of ring‐functionalized histidines in peptide‐based medicinal chemistry and drug discovery

“…Conformational and docking studies proved that the macrocycle's mimic β-strand geometry helped in its effective binding to the active site. 181 Sada et al 182 reported the synthesis and biological evaluation of mono and dihalogenated histamine, histidine and carnosine derivatives. The synthesized compounds were investigated as carbonic anhydrase (CA) activator in all its five forms viz.…”

“…The synthesized compounds were assayed against calpain 2 and peptide 198 (Figure 17) exhibited most promising activity with IC 50 value of 238 nM. Conformational and docking studies proved that the macrocycle's mimic β‐strand geometry helped in its effective binding to the active site 181 …”