Abstract
Fluorinated moieties are highly valuable to chemists due to the sensitive NMR detectability of the 19F nucleus. Fluorination of molecular scaffolds can also selectively influence a molecule’s polarity, conformational preferences and chemical reactivity, properties that can be exploited for various chemical applications. A powerful route for incorporating fluorine atoms in biomolecules is last-stage fluorination of peptide scaffolds. One of these methods involves esterification of the C-terminus of peptides using a diazomethane species. Here, we provide an investigation of the physicochemical consequences of peptide esterification with partially fluorinated ethyl groups. Derivatives of N-acetylproline are used to model the effects of fluorination on the lipophilicity, hydrolytic stability and on conformational properties. The conformational impact of the 2,2-difluoromethyl ester on several neutral and charged oligopeptides was also investigated. Our results demonstrate that partially fluorinated esters undergo variable hydrolysis in biologically relevant buffers. The hydrolytic stability can be tailored over a broad pH range by varying the number of fluorine atoms in the ester moiety or by introducing adjacent charges in the peptide sequence.
Highlights
Fluorine is a rare element in natural biochemical settings [1]
In accordance with previous reports, we found that the ethyl ester hydrolyzed 3 times slower compared with the methyl ester, whereas the introduction of the first fluorine atom dropped the half-life by a factor of approximately 8
The accelerated hydrolysis of oligolysine esters can potentially lead to partial 2,2-difluoroethyl ester hydrolysis during the circular dichroism (CD) sample handling, and explain somewhat reduces CD intensity compared to the methyl ester samples (Figure 5)
Summary
Fluorine is a rare element in natural biochemical settings [1]. Notwithstanding several prominent fluoro-organic metabolites in nature [2,3], fluorine is virtually absent from natural biopolymers such as proteins and nucleic acids. Perhaps the most studied molecules exhibiting such effects are the proline analogues, with the proline-to-fluoroproline exchange providing the first proof-of-principle and experimental basis for a number of subsequent conceptual studies [32] These were used to demonstrate the impact of non-canonical amino acids in proteins [33]. The impact of partially fluorinated alkyl groups on the polarity of small molecules was recently investigated in a series of model studies by Huchet and others [41,42,43,44] These investigations demonstrated the checkmark-shape of the lipophilicity (logP) changes upon increasing the number of fluorine atoms in the terminal aliphatic alkyl fragment (Figure 1A; see remark on page S2 in Supporting Information File 1). The conformational impact is examined using several oligopeptides
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