Cyclic Tetrapeptides from Nature and Design: A Review of Synthetic Methodologies, Structure, and Function

Abstract

Small cyclic peptides possess a wide range of biological properties and unique structures that make them attractive to scientists working in a range of areas from medicinal to materials chemistry. However, cyclic tetrapeptides (CTPs), which are important members of this family, are notoriously difficult to synthesize. Various synthetic methodologies have been developed that enable access to natural product CTPs and their rationally designed synthetic analogues having novel molecular structures. These methodologies include the use of reversible protecting groups such as pseudoprolines that restrict conformational freedom, ring contraction strategies, onresin cyclization approaches, and optimization of coupling reagents and reaction conditions such as temperature and dilution factors. Several fundamental studies have documented the impacts of amino acid configurations, N-alkylation, and steric bulk on both synthetic success and ensuing conformations. Carefully executed retrosynthetic ring dissection and the unique structural features of the linear precursor sequences that result from the ring dissection are crucial for the success of the cyclization step. Other factors that influence the outcome of the cyclization step include reaction temperature, solvent, reagents used as well as dilution levels. The purpose of this review is to highlight the current state of affairs on naturally occurring and rationally designed cyclic tetrapeptides, including strategies investigated for their syntheses in the literature, the conformations adopted by these molecules, and specific examples of their function. Using selected examples from the literature, an in-depth discussion of the synthetic techniques and reaction parameters applied for the successful syntheses of 12-, 13-, and 14-membered natural product CTPs and their novel analogues are presented, with particular focus on the cyclization step. Selected examples of the three-dimensional structures of cyclic tetrapeptides studied by NMR, and X-ray crystallography are also included. CONTENTSSpecial Issue: Macrocycles

Synthesis of cyclotetrapeptide analogues of c-PLAI and evaluation of their antimicrobial properties

“…The linear precursors were synthesized using a solid-phase Fmoc-chemistry method on a 2-chlorotrityl resin, while the cyclic products were obtained through cyclization of the linear peptides in the solution phase. The cyclization site always involved a proline residue at the N-terminus, because the proline residue is a β-turn inducer that can facilitate cyclization [6,7,14]. The synthesis of all peptides began with the attachment of isoleucine to the 2-chlorotrityl resin, which resulted in an isoleucine-resin with loading values in the range of 0.61-0.90 mmol g −1 (table 1).…”

“…During the coupling reactions in the presence of the HATU/HOAt reagent, it was found that triple coupling protocols were needed for the effective coupling between valine and isoleucine as well as between leucine and valine. The presence of the β-branched residue of valine could represent an issue in the synthesis [ 6 , 7 ]. The synthesis of all linear peptides resulted in percentage yields in the range of 29.9–60.8% ( table 1 ).…”

“…All analogues ( figure 1 ) were designed to retain proline in their structure, as several groups reported that proline is a key amino acid residue in various AMPs [ 4 , 5 ]. Proline has also been known to promote β-turn structure that favours cyclization [ 6 , 7 ]. Further modifications were introduced by replacing the amino acid leucine or alanine of c-PLAI with hydrophobic (valine, phenylalanine) or cationic (lysine) amino acids, thus resulting in five analogues, i.e.…”

Novel Methodologies for Chemical Activation in Organic Synthesis under Solvent-Free Reaction Conditions

“…As was mentioned above, peptide synthesis continues to be one of the areas of greatest interest in organic chemistry. This is due to the fact that peptides have many diverse applications, not only in the synthesis of organic compounds, but most importantly in the food and pharmaceutical industry [ 110 , 111 , 112 ]. In this regard, in recent years mechanochemistry has played an important role in the green synthesis of these compounds [ 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 ].…”

A Diversity‐Oriented Approach to Large Libraries of Artificial Macrocycles

“…This is especially the case when libraries of macrocyclic compounds obtained by cost-efficient parallel chemistry methods are considered. Many recent advances in this area were aimed at the synthesis of cyclic peptides or peptidomimetics, [12][13][14][15][16][17][18][19][20][21] other important success stories include the use of multicomponent reactions [21][22][23][24] and DNA-encoding technology. [25,26] Another synthetic methodology that is especially interesting for the construction of non-peptidic macrocycles is diversity-oriented synthesis (DOS).…”