Synthesis and Functionalization of Azetidine-Containing Small Macrocyclic Peptides

Saunders, GJ ORCID: 0000-0003-1265-8654, Spring, SA, Jayawant, E ORCID: 0000-0003-2193-5414, Wilkening, I, Roesner, S ORCID: 0000-0003-2143-4708, Clarkson, GJ, Dixon, AM, Notman, R and Shipman, M ORCID: 0000-0002-3349-5594 (2024) Synthesis and Functionalization of Azetidine-Containing Small Macrocyclic Peptides. Chemistry - A European Journal. pp. 1-7. ISSN 0947-6539

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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. 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 and Biomolecular Sciences
Publisher:	Wiley
Date of acceptance:	13 March 2024
Date of first compliant Open Access:	23 April 2024
Date Deposited:	23 Apr 2024 11:12
Last Modified:	04 Jul 2025 12:45
DOI or ID number:	10.1002/chem.202400308
URI:	https://researchonline.ljmu.ac.uk/id/eprint/23108

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