Kubyshkin Vladimir, Budisa Nediljko
Biocatalysis group, Institute of Chemistry, Technical University of Berlin, Müller-Breslau-Strasse 10, Berlin 10623, Germany.
Beilstein J Org Chem. 2017 Nov 16;13:2442-2457. doi: 10.3762/bjoc.13.241. eCollection 2017.
Fluorinated moieties are highly valuable to chemists due to the sensitive NMR detectability of the F 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 -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.
由于氟原子核具有灵敏的核磁共振可检测性，氟化部分对化学家来说具有很高的价值。分子支架的氟化还可以选择性地影响分子的极性、构象偏好和化学反应性，这些性质可用于各种化学应用。将氟原子引入生物分子的一种有效途径是肽支架的最后阶段氟化。其中一种方法涉及使用重氮甲烷物种对肽的C末端进行酯化。在此，我们对用部分氟化乙基进行肽酯化的物理化学后果进行了研究。使用α-乙酰基脯氨酸的衍生物来模拟氟化对亲脂性、水解稳定性和构象性质的影响。还研究了2,2-二氟甲酯对几种中性和带电荷寡肽的构象影响。我们的结果表明，部分氟化酯在生物相关缓冲液中会发生不同程度的水解。通过改变酯部分中的氟原子数量或在肽序列中引入相邻电荷，可以在很宽的pH范围内调整水解稳定性。
