The Library
Synthesis and functionalization of azetidine‐containing small macrocyclic peptides
Tools
Saunders, George J., Spring, Sam, Jayawant, Eleanor, Wilkening, Ina, Roesner, Stefan, Clarkson, Guy J., Dixon, Ann M., Notman, Rebecca and Shipman, Michael (2024) Synthesis and functionalization of azetidine‐containing small macrocyclic peptides. Chemistry – A European Journal . e202400308. doi:10.1002/chem.202400308 ISSN 1521-3765. (In Press)
|
PDF
WRAP-synthesis-functionalization-azetidine‐containing-small-macrocyclic-peptides-2024.pdf - Accepted Version - Requires a PDF viewer. Available under License Creative Commons Attribution 4.0. Download (1417Kb) | Preview |
Official URL: http://dx.doi.org/10.1002/chem.202400308
Abstract
Cyclic peptides are increasingly important structures in drugs but their development can be impeded by difficulties associated with their synthesis. Here, we introduce the 3-aminoazetidine (3-AAz) subunit as a new turn-inducing element for the efficient synthesis of small head-to-tail cyclic peptides. Greatly improved cyclizations of tetra-, penta- and hexapeptides (28 examples) under standard reaction conditions are achieved by introduction of this element within the linear peptide precursor. Post-cyclization deprotection of the amino acid side chains with strong acid is realized without degradation of the strained four-membered azetidine. An special feature of this chemistry is that further late-stage modification of the resultant macrocyclic peptides can be achieved via the 3-AAz unit. This is done by: (i) chemoselective deprotection and substitution at the azetidine nitrogen, or by (ii) a click-based approach employing a 2-propynyl carbamate on the azetidine nitrogen. In this way, a range of dye and biotin tagged macrocycles are readily produced. Structural insights gained by XRD analysis of a cyclic tetrapeptide indicate that the azetidine ring encourages access to the less stable, all-trans conformation. Moreover, introduction of a 3-AAz into a representative cyclohexapeptide improves stability towards proteases compared to the homodetic macrocycle.
Item Type: | Journal Article | ||||||
---|---|---|---|---|---|---|---|
Subjects: | Q Science > QD Chemistry | ||||||
Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||
Library of Congress Subject Headings (LCSH): | Cyclic peptides -- Synthesis, Chemistry, Organic, Macrocyclic compounds | ||||||
Journal or Publication Title: | Chemistry – A European Journal | ||||||
Publisher: | Wiley | ||||||
ISSN: | 1521-3765 | ||||||
Official Date: | 15 March 2024 | ||||||
Dates: |
|
||||||
Article Number: | e202400308 | ||||||
DOI: | 10.1002/chem.202400308 | ||||||
Status: | Peer Reviewed | ||||||
Publication Status: | In Press | ||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||
Date of first compliant deposit: | 26 March 2024 | ||||||
Date of first compliant Open Access: | 28 March 2024 | ||||||
RIOXX Funder/Project Grant: |
|
Request changes or add full text files to a record
Repository staff actions (login required)
View Item |
Downloads
Downloads per month over past year