Fluorinated amino acid

Nonenzymatic fluorinated amino acids (182) have been developed by enzymatic and chemical methods as bioactive compounds siace the antiviral effect of fluorinated alanine was found (183). 

Wadhwani P, Tremouilhac P, Strandberg E, Afonin S, Grage S, Ieronimo M, Berditsch M, Ulrich AS (2007) Using fluorinated amino acids for structure analysis of membrane-active peptides by solid-state 19F-NMR. In Soloshonok V, Mikami K, Yamazaki T, Welch JT, Honek J (eds) Current fluoroorganic chemistry (ACS symposium series). American Chemical Society, Washington, pp 431 146... 

Dynamic Kinetic Resolution Synthesis of a Fluorinated Amino Acid Ester Amide by a Continuous Process Lipase-mediated Ethanolysis of an Azalactone... 

Fluorinated amino acid with antibiotic property 195, 196... 

Remarkably, incorporation of fluorinated amino acids into proteins can also be accomplished in vivo. This supposes that the fluorinated amino acid analogs are recognized by the appropriate amino acyl-tRNA synthetase enzyme with efficiency similar to that of the natural amino acid. The proliferase response elicited by a fluorinated analog (a trifluoroisoleucine derivative) of murine interleukin-2 produced in an appropriate Escherichia coli strain was nearly as high as that of the authentic cytokine, indicating folding into an authentic, native structure [84],... 

C. Jackel, W. Seufert, S. Thust, B. Koksch, Evaluation ofthe molecular interactions of fluorinated amino acids with native polypeptides, ChemBioChem. 5 (2004) 717-720. 

Molecular Interactions of Fluorinated Amino Acids in a Native Polypeptide Environment... 

This chapter aims to summarize our efforts to investigate the effects of fluorinated amino acid substitutes on the interactions with natural protein environments. In addition to a rather specific example concerning the interactions of small peptides with a proteolytic enzyme, we present a simple polypeptide model that aids for a systematic investigation of the interaction pattern of amino acids that differ in side chain length as well as fluorine content within both a hydrophobic and hydrophilic protein environment. Amino acid side chain fluoiination highly affects polypeptide folding due to steric effects, polarization, and fluorous interactions. 

With the support of quantum mechanics this proteolysis study has readily shown that fluorinated amino acid side chains are able to direct enzyme substrate interactions, which can have an influence on proteolytic stability. Depending on the absolute stereochemistry and on the position within the sequence, aTfm amino acids can considerably stabilize peptides against proteolysis. The unique electrostatic properties of carbon-bound fluorine, however, may also induce a contrary effect. The conformational restrictions of C -dialkylation seem to be partly dimin-ishable by the electrostatic consequences of fluorination. With this knowledge. 

In the previous chapter we described a systematic study of the interactions of small model peptides with a rather specific enzyme. In our attempt to systematize the effects of fluorinated amino acids on peptide and protein interactions we have established a model system that lays the foundation for a more general approach. How do the steric effects and the degree of fluorination as well as the polarity of fluoroalkyl amino acid side chains affect the folding of proteins and the strength of peptide-protein interactions In order to answer this central question we choose a very common folding motive, the a-helical coiled coil. 

The a-helical coiled coil-based screening system already provided a wide variety of information about the interactions of fluorinated amino acids within hydrophobic and hydrophilic protein environments. Investigations on the thermal stability as well as the replicase activity have both emphasized the orthogonal properties of fluorinated aliphatic amino acid side chains. The term orthogonal in this context has been chosen by us to demonstrate that they are in fact hydrophobic... 

Being highly hydrophobic but less lipophilic than their hydrocarbon analogs, fluoroalkyl amino acid side chains tend to interact with one another by fluorine-fluorine contacts. Therefore, even one single fluorinated amino acid can direct polypeptide folding due to strong character of fluorine-fluorine interactions (Section 3.3 and 3.4). 

Interactions with metabolic enzymes fluorinated amino acids are peptidomi-metic units or reactive entities used to design either reversible enzyme inhibitors (analogues of substrates) or irreversible enzyme inhibitors (mechanism-based inhibitors). 

Lastly, when a fluorinated amino acid is incorporated into a peptide or a protein, the fluorine atoms can be used as probes in F NMR, and in medical imaging in the case of... 

The numerous applications of fluorinated amino acids in medicinal chemistry and in enzymology have induced a large number of studies dedicated to their synthesis. Synthetic chemists have provided protein biologists and chemists with an incredible range of fluorinated amino acids. Since this work has been covered in the literamre, we only review some representative examples of proteogenic fluorinated amino acid analogues, with special focus on the synthetic aspects proper to fluorine chemistry. The numerous fluorinated peptidomimetic units (e.g., amino alcohols) are not included in this chapter. 

First, we consider the fluorinated analogues of natural amino acids, where at least one or several hydrogen atoms have been replaced by fluorine atoms. Then we consider amino acids substituted by a fluoroalkyl group, as the sole structural modification, with special focus on a-fluorinated amino acids. Lastly, we give an outline of polypeptides and proteins in which fluorinated amino acids have been incorporated. 

Numerous nonproteogenic a- or jS-fluorinated amino acids and amino alcohols have been prepared as peptidomimetic units. Unfortunately, due to lack of space, they have not been included in this book. Recent reviews have been dedicated to some of these compounds. ... 

INCORPORATION OF FLUORINATED AMINO ACIDS INTO PEPTIDES AND PROTEINS... 

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