Light-mediated synthesis of azepine-linked peptide macrocycles
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[EMBARGOED UNTIL 12/01/2025] Conformationally constrained macrocyclic peptides exhibit improved stability, target affinity, and cell permeability compared to their linear counterparts, making them excellent candidates for drug development. This unique class of compounds holds significant pharmaceutical promise, and consequently, numerous peptide cyclization methods have been developed to optimize these properties. In this work, we introduce a straightforward, visible light-induced cyclization method that selectively creates a covalent bond between a seven-membered ring ketenimine intermediate and a lysine residue, yielding an azepine-linked cyclic peptide. We successfully synthesized a library of cyclic peptides ranging from 4 to 10 residues with good to moderate isolated yields. To further demonstrate the chemoselectivity of this method, several cyclic peptides containing various reactive side chains were synthesized and isolated, also achieving good to moderate yields. Additionally, we tested the compatibility of our method with a more complex 13-residue p53-derived peptide, which resulted in successful cyclization. Finally, three cilengitide-type cyclic peptides containing RGD residues were designed and synthesized using our method and are set to be evaluated for anti-cancer activity. Each starting linear peptide, and its corresponding cyclic product was characterized by high-resolution mass spectrometry, and purity was confirmed through analytical HPLC. H1NMR experiment was conducted for one of the Linear peptides and its cyclic peptide counterparts, proving the successful formation of cyclic form peptide.
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M.S.