Template-induced macrocycle diversity through large ring-forming alkylations of tryptophan

Lawson, Kenneth V.; Rose, Tristan E.; Harran, Patrick G.

doi:10.1016/j.tet.2013.05.060

Cited by 28 publications

(27 citation statements)

References 100 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 8 To our knowledge, synthesis of macrocyclic pyrroloindolines by intramolecular indole C3 substitution is limited to one example in an initial communication by us ( vide infra ). 9 The present study accesses six new products bearing these motifs, as well as thirty-nine additional indolic macrocycle isomers, and characterizes their structures and reactivity in detail.…”

Section: Introductionmentioning

confidence: 99%

“…In a recent study of internal alkylations of tryptophan-containing peptides, we characterized the products derived from acidolysis of composite oligomer 2 ( Scheme 1 ). 9 When treated with Brønsted or Lewis acid, degradation of the cinnamyl carbonate in 2 led to competing internal Friedel–Crafts alkylations of proximal tryptophan and tyrosine side chains. The distribution of products was sensitive to acid promoter, solvent and temperature.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

On the prevalence of bridged macrocyclic pyrroloindolines formed in regiodivergent alkylations of tryptophan

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

On the prevalence of bridged macrocyclic pyrroloindolines formed in regiodivergent alkylations of tryptophan

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“… 28 Notable recent examples come from the research groups of Wessjohann, 28 , 29 Marcaurelle, 30 Marsault 9 and Harran. 31 Overall however, there still remains a relative lack of DOS strategies that are specifically directed towards macrocyclic peptidomimetics. Reports beyond the proof-of-principle stage (that is, involving the application of such DOS strategies for the generation of large numbers of structurally diverse compounds based around a variety of macrocyclic peptidomimetic ring architectures) are rare.…”

Section: Introductionmentioning

confidence: 99%

A diversity-oriented synthesis strategy enabling the combinatorial-type variation of macrocyclic peptidomimetic scaffolds

et al. 2015

View full text Add to dashboard Cite

show abstract

“…We observed that decomposition of a cinnamyl carbonate within the template could capture pendant tyrosine residues to form cyclic ethers (51,54). This result followed from catalysis pioneered by Tsuji and Trost.…”

mentioning

confidence: 97%

Template-constrained macrocyclic peptides prepared from native, unprotected precursors

Lawson

Rose

Harran

2013

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

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Template-induced macrocycle diversity through large ring-forming alkylations of tryptophan

Cited by 28 publications

References 100 publications

On the prevalence of bridged macrocyclic pyrroloindolines formed in regiodivergent alkylations of tryptophan

On the prevalence of bridged macrocyclic pyrroloindolines formed in regiodivergent alkylations of tryptophan

A diversity-oriented synthesis strategy enabling the combinatorial-type variation of macrocyclic peptidomimetic scaffolds

Template-constrained macrocyclic peptides prepared from native, unprotected precursors

Contact Info

Product

Resources

About