Cyclotetrapeptides and cyclopentapeptides: occurrence and synthesis*

Schmidt, Ulrich; Langner, Jörg

doi:10.1111/j.1399-3011.1997.tb01122.x

Cited by 123 publications

(77 citation statements)

References 75 publications

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“…The inner salts invoked here as intermediates formed at low concentration would likewise be expected to offset entropic costs associated with ring formation (64,65). It is also consistent with a general lack of oligomeric products formed in the catalysis, which can limit other peptide cyclization methods (45,66,67). High macrocyclization efficiency (calculated Emac index = 7.77) (68) was observed at 20-fold higher concentration (0.1 M), wherein the isolated yield was lowered only slightly ( Fig.…”

Section: Resultssupporting

confidence: 77%

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Template-constrained macrocyclic peptides prepared from native, unprotected precursors

Lawson

Rose

Harran

2013

Proc. Natl. Acad. Sci. U.S.A.

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Peptide-protein interactions are important mediators of cellularsignaling events. Consensus binding motifs (also known as short linear motifs) within these contacts underpin molecular recognition, yet have poor pharmacological properties as discrete species. Here, we present methods to transform intact peptides into stable, templated macrocycles. Two simple steps install the template. The key reaction is a palladium-catalyzed macrocyclization. The catalysis has broad scope and efficiently forms large rings by engaging native peptide functionality including phenols, imidazoles, amines, and carboxylic acids without the necessity of protecting groups. The tunable reactivity of the template gives the process special utility. Defined changes in reaction conditions markedly alter chemoselectivity. In all cases examined, cyclization occurs rapidly and in high yield at room temperature, regardless of peptide composition or chain length. We show that conformational restraints imparted by the template stabilize secondary structure and enhance proteolytic stability in vitro. Palladium-catalyzed internal cinnamylation is a strong complement to existing methods for peptide modification. S ynthetic peptides and peptidomimetics play wide-ranging roles in pharmacology and drug discovery. Interest in these substances continues to grow, particularly as medicinal chemistry pushes further into control of cellular-signaling events mediated by protein-protein interactions (PPIs) (1-3). The subset of socalled "druggable" PPIs includes those mediated by consensus peptides, where binding determinants are localized within defined motifs (4-8). Experimental data as well as computational/ bioinformatic efforts (9-11) to identify "short linear motifs" within signaling proteins suggest that the number of druggable PPIs has been underestimated (12, 13). Considerable opportunity exists for new chemistry in this area (14). Synthetic peptides that target "hot spots" on protein surfaces are a logical entry to drug-discovery programs (15-19). However, native peptides generally have poor pharmacological properties (20). Modifications that offset those limitations while stably recapitulating proteinbinding conformations are of considerable interest (14,(21)(22)(23).Ring-forming reactions are prominent among alterations found to improve the stability and performance of peptides (24-27). They find broad utility in synthesis and, increasingly, in combination with phage, ribosome, and mRNA display technologies (28-32). Relative to their acyclic counterparts, cyclic peptides have more defined conformations and are less prone to aggregate (33). Head-to-tail lactamization is the most common method to synthesize cyclic peptides (34-36). Internal disulfide bonding is also used (37, 38), as are newer techniques such as ring-closing olefin metathesis (39) and catalyzed cycloaddition of azides to alkynes (40-42). These procedures rely on judicious use of protecting groups and/or tailored amino acid residues (Fig. 1A) (43, 44). Careful attention must be paid to...

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Section: Resultssupporting

confidence: 77%

“…Careful attention must be paid to substrate conformational biases to avoid competing oligomerization. Moreover, lactamization of peptides shorter than five residues can be particularly difficult (34,45). …”

mentioning

confidence: 99%

Template-constrained macrocyclic peptides prepared from native, unprotected precursors

Lawson

Rose

Harran

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…This rather modest yield was significantly higher than the yields obtained for the cyclization of the same peptide in solution phase (Schmidt and Langner, 1997). The naturally occurring cycloheptapeptide Stylostatin 1 was also cyclized following this approach with 7% overall yield.…”

Section: Synthesis Of Backbone Cyclic Peptidesmentioning

confidence: 77%

The Use of Aryl Hydrazide Linkers for the Solid‐Phase Synthesis of Chemically Modified Peptides

2007

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Since Merrifield introduced the concept of solid phase synthesis in 1963 for the rapid preparation of peptides, a large variety of different supports and resin-linkers have been developed that improve the efficiency of peptide assembly and expand the myriad of synthetically feasible peptides. The aryl hydrazide is one of the most useful resin-linkers for the synthesis of chemically modified peptides. This linker is completely stable during Boc-and Fmoc-based solid phase synthesis and yet it can be cleaved under very mild oxidative conditions. The present article reviews the use of this valuable linker for the rapid and efficient synthesis of C-terminal modified peptides, head-to-tail cyclic peptides and lipidated peptides.

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“…[3] These approaches have frequently been complicated by low efficiencies in peptide ring closures, caused by various side reactions upon cyclization of the open tetrapeptide, including epimerization of one or more stereocenters, as well as the preferential formation of dimeric octapeptides. [4] In general, macrolactam formation between the C-terminus of proline and the N-terminus of Aoda is crucial in such an approach, and all known synthetic studies have demonstrated that cyclization does not occur at any other position. [3,4] As part of our investigation into the synthesis of apicidin analogues, we became interested in the possibility of using macrocyclization by ring-closing metathesis (RCM) [5] and subsequent hydrogenation of a suitably protected diene 3, followed by transannular ring closure [6] of intermediate 2 to give the target tetrapeptides 1 (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%

Ring‐Closing Metathesis in the Synthesis of Biologically Active Peptidomimetics of Apicidin A

et al. 2007

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Syntheses of novel 16-membered macrocyclic peptidomimetics are reported, which employ iterative peptide coupling followed by high yielding ring-closing metathesis (RCM) as the key cyclization step. The target macrocyclic compounds include examples containing a (2S)-amino-8-oxodecanoic acid (Aoda) residue as analogues of apicidin A, a known potent histone deacetylase (HDAC) inhibitor. These showed modest levels of biological activity as HDAC inhibitors.

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Cyclotetrapeptides and cyclopentapeptides: occurrence and synthesis*

Cited by 123 publications

References 75 publications

Template-constrained macrocyclic peptides prepared from native, unprotected precursors

Template-constrained macrocyclic peptides prepared from native, unprotected precursors

The Use of Aryl Hydrazide Linkers for the Solid‐Phase Synthesis of Chemically Modified Peptides

Ring‐Closing Metathesis in the Synthesis of Biologically Active Peptidomimetics of Apicidin A

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