The development and application of a novel safety-catch linker for BOC-based assembly of libraries of cyclic peptides

Bourne, Gregory T., Golding, Simon W., McGeary, Ross P., Meutermans, Wim D. F., Jones, Alun, Marshall, Garland R., Alewood, Paul F. and Smythe, Mark L. (2001) The development and application of a novel safety-catch linker for BOC-based assembly of libraries of cyclic peptides. Journal of Organic Chemistry, 66 23: 7706-7713. doi:10.1021/jo010580y

Author Bourne, Gregory T.
Golding, Simon W.
McGeary, Ross P.
Meutermans, Wim D. F.
Jones, Alun
Marshall, Garland R.
Alewood, Paul F.
Smythe, Mark L.
Title The development and application of a novel safety-catch linker for BOC-based assembly of libraries of cyclic peptides
Journal name Journal of Organic Chemistry   Check publisher's open access policy
ISSN 0022-3263
Publication date 2001-01-01
Year available 2001
Sub-type Article (original research)
DOI 10.1021/jo010580y
Open Access Status
Volume 66
Issue 23
Start page 7706
End page 7713
Total pages 8
Editor C. D. Poulter
Place of publication Washington
Publisher American Chemical Society
Language eng
Subject C1
250302 Biological and Medical Chemistry
670403 Treatments (e.g. chemicals, antibiotics)
250301 Organic Chemical Synthesis
Abstract Cyclic peptides are appealing targets in the drug-discovery process. Unfortunately, there currently exist no robust solid-phase strategies that allow the synthesis of large arrays of discrete cyclic peptides. Existing strategies are complicated, when synthesizing large libraries, by the extensive workup that is required to extract the cyclic product from the deprotection/cleavage mixture. To overcome this, we have developed a new safety-catch linker. The safety-catch concept described here involves the use of a protected catechol derivative in which one of the hydroxyls is masked with a benzyl group during peptide synthesis, thus making the linker deactivated to aminolysis. This masked derivative of the linker allows BOC solid-phase peptide assembly of the linear precursor. Prior to cyclization, the linker is activated and the linear peptide deprotected using conditions commonly employed (TFMSA), resulting in deprotected peptide attached to the activated form of the linker. Scavengers and deprotection adducts are removed by simple washing and filtration. Upon neutralization of the N-terminal amine, cyclization with concomitant cleavage from the resin yields the cyclic peptide in DMF solution. Workup is simple solvent removal. To exemplify this strategy, several cyclic peptides were synthesized targeted toward the somatostatin and integrin receptors. From this initial study and to show the strength of this method, we were able to synthesize a cyclic-peptide library containing over 400 members. This linker technology provides a new solid-phase avenue to access large arrays of cyclic peptides.
Keyword Chemistry, Organic
Solid-phase Synthesis
High-affinity Ligands
Drug Discovery
Combinatorial Technologies
Molecular Diversity
Aqueous Buffers
Q-Index Code C1
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 33 times in Thomson Reuters Web of Science Article | Citations
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Created: Wed, 15 Aug 2007, 02:24:21 EST