ArticleThe Journal of organic chemistry2014
Unexpected hydrolytic instability of N-acylated amino acid amides and peptides.
Article in The Journal of organic chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
What it found
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Who cites it
9 citing papers in PubMed, 25 citations in OpenAlex.
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- Structure-Acid Lability Relationship ofMolecules (Basel, Switzerland) · 2021Article
- Multi-Institution Research and Education Collaboration Identifies New Antimicrobial Compounds.ACS chemical biology · 2020Article
- Amide Bond Activation of Biological Molecules.Molecules (Basel, Switzerland) · 2018Review
- Documenting and harnessing the biological potential of molecules in Distributed Drug Discovery (D3) virtual catalogs.Chemical biology & drug design · 2017Article
- Surface-enhanced Raman scattering investigation of targeted delivery and controlled release of gemcitabine.International journal of nanomedicine · 2017Article
- Solid-Phase Synthesis of Amine/Carboxyl Substituted Prolines and Proline Homologues: Scope and Limitations.Molecules (Basel, Switzerland) · 2016Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Remote amide bonds in simple N-acyl amino acid amide or peptide derivatives 1 can be surprisingly unstable hydrolytically, affording, in solution, variable amounts of 3 under mild acidic conditions, such as trifluoroacetic acid/water mixtures at room temperature. This observation has important implications for the synthesis of this class of compounds, which includes N-terminal-acylated peptides. We describe the factors contributing to this instability and how to predict and control it. The instability is a function of the remote acyl group, R(2)CO, four bonds away from the site of hydrolysis. Electron-rich acyl R(2) groups accelerate this reaction. In the case of acyl groups derived from substituted aromatic carboxylic acids, the acceleration is predictable from the substituent's Hammett σ value. N-Acyl dipeptides are also hydrolyzed under typical cleavage conditions. This suggests that unwanted peptide truncation may occur during synthesis or prolonged standing in solution when dipeptides or longer peptides are acylated on the N-terminus with electron-rich aromatic groups. When amide hydrolysis is an undesired secondary reaction, as can be the case in the trifluoroacetic acid-catalyzed cleavage of amino acid amide or peptide derivatives 1 from solid-phase resins, conditions are provided to minimize that hydrolysis.
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Registered trials
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