A versatile synthetic approach to peptidyl privileged structures using a "safety-catch" linker.
Peptidyl privileged structures have been widely used by many groups to discover biologically active molecules. In this context, privileged substructures are used as "hydrophobic anchors", to which peptide functionality is appended to gain specificity. Utilization of this concept has led to the discovery of many different active compounds at a wide range of biological receptors. A synthetic approach to these compounds has been developed on a "safety-catch" linker that allows rapid preparation of large libraries of these molecules. Importantly, amide bond formation/cleavage through treatment with amines is the final step; it is a linker strategy that allows significant diversification to be easily incorporated, and it only requires the inclusion of an amide bond. In addition, chemistry has been developed that permits the urea moiety to be inserted at the N-terminus of the peptide, allowing the same set of amines (either privileged substructures or amino acid analogues) to be used at both the N- and C-termini of the molecule. To show the robustness of this approach, a small library of peptidyl privileged structures were synthesized, illustrating that large combinatorial libraries can be synthesized using these technologies.
Horton
Douglas A
DA
Institute for Molecular Bioscience, The University of Queensland, St. Lucia, 4072 Queensland, Australia.
Severinsen
Rune
R
Kofod-Hansen
Mikael
M
Bourne
Gregory T
GT
Smythe
Mark L
ML
D000577:Amides / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D057927:Hydrophobic and Hydrophilic Interactions; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis*; D004364:Pharmaceutical Preparations; D013329:Structure-Activity Relationship
D000577:Amides; D000588:Amines; D019151:Peptide Library; D010455:Peptides; D004364:Pharmaceutical Preparations