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Synthesis and Functionalization of Azetidine-Containing Small Macrocyclic Peptides

Saunders, GJ, Spring, SA, Jayawant, E, Wilkening, I, Roesner, S, Clarkson, GJ, Dixon, AM, Notman, R and Shipman, M (2024) Synthesis and Functionalization of Azetidine-Containing Small Macrocyclic Peptides. Chemistry - A European Journal. pp. 1-7. ISSN 0947-6539

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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. A 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: Article
Uncontrolled Keywords: azetidine; cyclic peptides; functionalization; macrocyclization; peptidomimetics; 03 Chemical Sciences; General Chemistry
Subjects: Q Science > QD Chemistry
R Medicine > RS Pharmacy and materia medica
Divisions: Pharmacy & Biomolecular Sciences
Publisher: Wiley
SWORD Depositor: A Symplectic
Date Deposited: 23 Apr 2024 11:12
Last Modified: 23 Apr 2024 13:10
DOI or ID number: 10.1002/chem.202400308
URI: https://researchonline.ljmu.ac.uk/id/eprint/23108
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