Contemporary strategies for peptide macrocyclization

Abstract

Peptide macrocycles have found applications that range from drug discovery to nanomaterials. These ring-shaped molecules have shown remarkable capacity for functional fine-tuning. Such capacity is enabled by the possibility of adjusting the peptide conformation using the techniques of chemical synthesis. Cyclic peptides have been difficult, and often impossible, to prepare using traditional synthetic methods. For macrocyclization to occur, the activated peptide must adopt an entropically disfavoured pre-cyclization conformation before forming the desired product. Here, we review recent solutions to some of the major challenges in this important area of contemporary synthesis.

Macrocyclic Peptoid–Peptide Hybrids as Inhibitors of Class I Histone Deacetylases

“…In contrast to the low yields obtained in the macrolactamization of 12-membered ring peptides, 36 the efficiency of the ring-closure was generally good as judged by LC-MS analysis, similar to that observed for 13-membered ring α 3 β peptides (typical overall isolated yields were 10−18%, Table S1). 1−6 HDAC inhibitory activity was initially assessed using HeLa cell nuclear extract.…”

Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications

“…154 The turn-like structure of 1,5-disubstituted 1,2,3-triazoles makes them excellent motifs for incorporation into macrocycles. 155 Two different strategies can be employed for the introduction of a 1,5-disubstituted triazole in a macrocycle. Either the triazole formation can be used in the macrocyclization step or the 1,5-triazole moiety can be introduced prior to the cyclization step.…”

Design, synthesis, and biological evaluation of scaffold-based tripeptidomimetic antagonists for CXC chemokine receptor 4 (CXCR4)

“…10 Moreover, head-to-tail cyclization of peptides is known to be facilitated by incorporation of a D-amino acid in an all-L sequence due to a turn-inducing effect. 15 For these reasons, we decided to focus on the D-Arg 1 epimers in the present study, using the lead cyclopentapeptide 2 (cyclo(-D-Arg 1 -Arg 2 -2-Nal 3 -Gly 4 -D-Tyr 5 -), Figure 2A) as starting point.…”