Synthesis of enantiomerically pure (2S,3S)-5,5,5-trifluoroisoleucine and (2R,3S)-5,5,5-trifluoro-allo-isoleucine

Erdbrink, Holger; Nyakatura, Elisabeth K.; Huhmann, Susanne; Gerling, Ulla I. M.; Lentz, Dieter; Koksch, Beate; Czekelius, Constantin

doi:10.3762/bjoc.9.236

Cited by 19 publications

(21 citation statements)

References 33 publications

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“…Leu and Ile are larger and more hydrophobic than Ala. The fluorinated amino acids are even larger and more hydrophobic than their hydrocarbon analogues [ 44 – 45 ]. Furthermore, fluorine substitution has been shown to polarize neighboring C–H bonds (here the γ-hydrogens) that could affect noncovalent interactions [ 9 , 11 ].…”

Section: Resultsmentioning

confidence: 99%

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Position-dependent impact of hexafluoroleucine and trifluoroisoleucine on protease digestion

Huhmann¹,

Stegemann²,

Folmert³

et al. 2017

Beilstein J. Org. Chem.

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Rapid digestion by proteases limits the application of peptides as therapeutics. One strategy to increase the proteolytic stability of peptides is the modification with fluorinated amino acids. This study presents a systematic investigation of the effects of fluorinated leucine and isoleucine derivatives on the proteolytic stability of a peptide that was designed to comprise substrate specificities of different proteases. Therefore, leucine, isoleucine, and their side-chain fluorinated variants were site-specifically incorporated at different positions of this peptide resulting in a library of 13 distinct peptides. The stability of these peptides towards proteolysis by α-chymotrypsin, pepsin, proteinase K, and elastase was studied, and this process was followed by an FL-RP-HPLC assay in combination with mass spectrometry. In a few cases, we observed an exceptional increase in proteolytic stability upon introduction of the fluorine substituents. The opposite phenomenon was observed in other cases, and this may be explained by specific interactions of fluorinated residues with the respective enzyme binding sites. Noteworthy is that 5,5,5-trifluoroisoleucine is able to significantly protect peptides from proteolysis by all enzymes included in this study when positioned N-terminal to the cleavage site. These results provide valuable information for the application of fluorinated amino acids in the design of proteolytically stable peptide-based pharmaceuticals.

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Section: Resultsmentioning

confidence: 99%

“…These results indicate that Leu, HfLeu, as well as Ile are well accommodated in the S2 subsite of pepsin. In contrast, TfIle, although smaller than HfLeu [ 44 ], doesn’t appear to fit well into the S2 pocket of pepsin.…”

Section: Resultsmentioning

confidence: 99%

Position-dependent impact of hexafluoroleucine and trifluoroisoleucine on protease digestion

Huhmann¹,

Stegemann²,

Folmert³

et al. 2017

Beilstein J. Org. Chem.

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“…We find that the dimeric oligomerization state of the parent system is retained when any one of the three fluorinated VPK variants assembles with VPE (Table 1 [26,28], and since coiled-coil formation is driven by the hydrophobic effect, it would be expected that the substitution of a hydrophobic core position with these amino acids lead to a stabilization of the VPE/VPK system [22]. Indeed, on the basis of the melting temperatures, a higher thermal stability is observed for VPE/VPK-5 3 ,5' 3 - seems to have only a minor influence.…”

Section: Resultsmentioning

confidence: 97%

“…In the parallel heterodimeric VPE/VPK model system the fluorinated residues exclusively interact with natural amino acids, that is, the central hydrophobic positions a' 16 , d' 19 , and a' 23 of VPE directly interact with the substituted position d 19 of VPK. Therefore the enhancement in the thermal stability for the 5 3 ,5' 3 -F 6 Leu containing analogue is likely a result of greater hydrophobicity [28] and efficient packing with the hydrocarbon side chains in the hydrophobic core.…”

Section: Resultsmentioning

confidence: 97%

Effects of single substitutions with hexafluoroleucine and trifluorovaline on the hydrophobic core formation of a heterodimeric coiled coil

Huhmann

Nyakatura

Erdbrink

et al. 2015

Journal of Fluorine Chemistry

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“…Also, over 90 % of α 4 H was degraded within 2 h when incubated with chymotrypsin, whereas α 4 F 6 is largely resistant to proteolytic cleavage by this enzyme. The authors suggest that these observations are best explained by the greater hydrophobicity of HfLeu, which stabilizes the fluorinated protein, rather than the fluorous effect, and the inability of proteases to accommodate fluorinated substrates …”

Section: Fluorinated Amino Acids For Influencing the Stability Of mentioning

confidence: 99%

Fine‐Tuning the Proteolytic Stability of Peptides with Fluorinated Amino Acids

Huhmann

Koksch

2018

Eur J Org Chem

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The decoration of organic compounds with fluorine substituents is a strategy well‐known to medicinal chemists. Around 25 % of drugs on the market contain at least one fluorine atom, as fluorine's unique properties very often produce effects that cannot be achieved by any other known functional group. The changes in molecular properties due to the incorporation of fluorine most relevant to medicinal chemistry are conformation, pKa values of neighboring functional groups, and interaction with proteins and membranes. The introduction of fluorine dramatically impacts these and in turn the pharmacokinetics and biological half‐lives of not only small molecules but peptides, which show high binding affinity and selectivity for their target and are, therefore, also desirable lead compounds in drug development. Unfortunately, several factors can limit the efficacy of peptides and biologicals including low bioavailability and protease digestion. Although the literature has numerous examples showing that fluorine can improve the latter aspect, there are also cases to the contrary. This review aims to provide an overview of the influence of fluorinated amino acids on the proteolytic stability of peptides.

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Synthesis of enantiomerically pure (2S,3S)-5,5,5-trifluoroisoleucine and (2R,3S)-5,5,5-trifluoro-allo-isoleucine

Cited by 19 publications

References 33 publications

Position-dependent impact of hexafluoroleucine and trifluoroisoleucine on protease digestion

Position-dependent impact of hexafluoroleucine and trifluoroisoleucine on protease digestion

Effects of single substitutions with hexafluoroleucine and trifluorovaline on the hydrophobic core formation of a heterodimeric coiled coil

Fine‐Tuning the Proteolytic Stability of Peptides with Fluorinated Amino Acids

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