Heteroaryl Rings in Peptide Macrocycles

Abstract

This Review is devoted to the chemistry of macrocyclic peptides having heterocyclic fragments in their structure. These motifs are present in many natural products and synthetic macrocycles designed against a particular biochemical target. Thiazole and oxazole are particularly common constituents of naturally occurring macrocyclic peptide molecules. This frequency of occurrence is because the thiazole and oxazole rings originate from cysteine, serine, and threonine residues. Whereas other heteroaryl groups are found less frequently, they offer many insightful lessons that range from conformational control to receptor/ligand interactions. Many options to develop new and improved technologies to prepare natural products have appeared in recent years, and the synthetic community has been pursuing synthetic macrocycles that have no precedent in nature. This Review attempts to summarize progress in this area.

Enzyme‐Primed Native Chemical Ligation Produces Autoinducing Cyclopeptides in Clostridia

“…Moreover, it represents a stabilized analogue of the cAIP intermediate thiolactone 1 and is not prone to hydrolysis. Heterocyclic motifs are present in many natural products and their incorporation in cyclic peptides has led to molecules with improved properties [24] …”

Naturally Occurring Oxazole-Containing Peptides

“…Bistratamides C, D, G, H, I, M, and N (12)(13)(14)(15)(16)(17)(18) are cyclic hexapeptides that were isolated from the cytotoxic extract from the ascidian Lissoclinum bistratum (Figure 7) [39,40]. Sharing a similar cyclic backbone, the structures of 12-18 were determined by means of 2D NMR spectroscopy, as well as mass spectrometry.…”

“…The presence of oxazole moieties in natural peptides confers stability and/or electronic distribution to the peptide chain, thereby enabling peptide-protein recognition and DNA/RNA-peptide interactions [7]. Furthermore, oxazoles show antibacterial [8,9], antiviral [10], antimalarial [11], and anti-algal properties [12], as well as cytotoxic activity [13], among others [14].…”

Grafting Bis(heteroaryl) Motifs into Ring Structures

“…This connectivity could potentially confer distinct conformational properties. Heterocyclic grafts in peptide macrocycles are known to reduce conformational flexibility through the introduction of an sp 2 ‐rich segment within the macrocyclic backbone , . In the case of cyclo‐GFGAH, the 1 H NMR spectrum hydrogen‐bonding pattern of the N τ ‐regioisomer was compared with a homedetic analog by variable temperature 1 H NMR (Figure A ).…”