CuAAC-Mediated Peptide Backbone Modification Strategies

CuAAC-Mediated Peptide Backbone Modification Strategies 

The metabolic stability of peptides is generally relatively low, which can be a drawback for therapeutic use. Approaches to increase the metabolic stability include backbone modifications, such as the introduction of amide bond isosteres (e.g., sulfonamides), N-alkylation, incorporation of nonproteinogenic or D-amino acids, and the use of dialkylated amino acids. More recently, the replacement of amide bonds with triazole isosteres has also become a viable strategy to modify 

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containing a triazole, an oxazole, a thiazole, or a pseudoproline moiety. Four of these analogs (39 to 32) were tested on their cytotoxicity relative to 28. Triazole 29 exhibited cytotoxicity at the same level as 28 with the thiazole derivative as a close second one. Pseudoprohne 32 showed a significant decrease in cytotoxicity, which was explained by the cis-locked pseudoprohne moiety disturbing the shape of trans-bonded 28. While thiazole 31 exhibited a cytotoxicity close to that of 28, oxazole 30 scored nearly as low as the pseudoprohne, explained by Davis et al., with the difference in flexibility between the two compounds. 

When a triazole moiety was used instead, an affinity was observed (fCj = 89 nM) that ranked between the values for the -alkene and ester, Ai-methyl amide and 

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