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A role for ring‐closing metathesis in medicinal chemistry: Mimicking secondary architectures in bioactive peptides
Author(s) -
Pérez de Vega María Jesús,
GarcíaAranda María Isabel,
GonzálezMuñiz Rosario
Publication year - 2011
Publication title -
medicinal research reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.868
H-Index - 130
eISSN - 1098-1128
pISSN - 0198-6325
DOI - 10.1002/med.20199
Subject(s) - chemistry , ring closing metathesis , disulfide bond , peptide , salt metathesis reaction , combinatorial chemistry , cyclic peptide , thioether , metathesis , click chemistry , computational biology , stereochemistry , biochemistry , organic chemistry , biology , polymerization , polymer
Synthetically versatile and easy to carry out, Ring‐Closing Metathesis (RCM) constitutes an attractive chemical tool, easily amenable for multiple substrates in mild conditions. In medicinal chemistry, the use of RCM has been especially prolific during the last few years. An important application that has benefited from this reaction is the stabilization of spatial conformations in bioactive peptides, since their 3D arrangements play relevant roles in biomolecular recognition processes. RCM reaction is being widely used to introduce conformational constraints into small peptides, through the generation of cyclic structures from appropriate linear precursors. As an alternative to strategies like disulfide or lactam‐bridged cyclizations, RCM shows the additional advantage of generating hydrocarbon bridges, less prone to metabolic degradation, and metabolically more stable, which could benefit their pharmacokinetic properties. Particularly remarkable is the application of RCM to the preparation of small peptide modulators able to mimic epitopes identified as hotspots within the surface contact areas in protein‐protein interactions (PPIs). This review deals with the replacement of S‐S and thioether linkages of cyclic peptides by C‐C‐bridges and with the stabilization of peptide secondary architectures (α‐helix, β‐hairpins, β‐turns) through RCM, as a useful strategy for the modulation of therapeutically relevant signaling pathways. © 2010 Wiley Periodicals, Inc. Med Res Rev 31: 677‐715, 2011