Fluorine-containing peptides

Synthesis and Biochemical Applications of Fluorine-Containing Peptides and Proteins ... 

Cieplack, P., Kollmann, P. A. and Radomski, J. P. (1996) Molecular design of fluorine-containing peptide mimetics, in Biomedicinal Frontiers of Fluorine Chemistry, ACS Symposium Series 639, American Chemical Society, Washington, D.C., pp. 143-156. 

Vine, W. H., Hsieh, K. H. and Marshall, G. R. (1981) Synthesis of fluorine-containing peptides - analogs of Angiotensin-II containing hexafluorovaline. Journal of Medicinal Chemistry, 24(9), 1043-1047. 

Levine-Pinto, H., Bouabdallah, B., Morgat, J. L., el al. (1981) Specific and direct fluorination of an histidine-containing peptide thyroliberin. Biochemical and Biophysical Research Communications, 103, 1121-1130. 

Amino-4-trifluorocumarin and its amino acid and peptide salts are used for fluorescent labeling of amino acids and peptides in biological studies (80JOC2283). Fluorine-containing triazoles are used to protect metals and alloys from atmospheric and salt corrosion (Scheme 1). 

Relaxation-related work on proteins and polypeptides makes typically use of H, and NMR. A couple of papers have dealt with measurements on in fluorine-labelled aminoacids incorporated into peptide stuctures. Shi and co-workers introduced, at some specific sites, an unnatural fluorine-containing aminoacid and a nitroxide spin-label into a multidomain protein known to exist in different conformations. Measurements of F PRE allowed to determine the conformation under different conditions. Suzuki et used another fluorine-containing amino acid, inserted into different parts of a membrane-active peptide, as a local dynamics probe. They measured F transverse relaxation to examine changes in the mobility in different regions of the peptide upon binding to a lipid bilayer. 

Figure 9.2. Schematic representation of the oxime-driven photopatteming of fluorine and peptide containing aminooxy species onto silicon wafers a) and ToF-SlMS ion maps of the fluorine b) and peptide c) species. The disappearance of the original NO2 species is also shown. The reaction sequence can be found in Figure 9.1(a). Reproduced with kind permission from Wiley-VCH from [PAU 12a]. For a color version of this figure, see WWW. iste.co. uk/lalevee/dye.zip...

An alternative to the use of [ F]SFB, which limits the identity of the final product, comes in the form of fluorine-18 labeled molecules specifically designed to possess a terminal alkyne, which allows for the use of so-called click chemistry to link the labeled molecule with either an azide containing peptide or an azide containing small molecule... 

The naturally occurring aromatic amino acids phenylalanine, tryptophane and tyrosine (Fig. 1) have been labelled with fluorine-18 through similar electrophilic substitution methods [7]. Aromatic residues contained in peptides have been labelled with CH3C02[ F]F [105,106], an example of direct labelling of macromolecules. However, direct labelling of macromolecules is usually not the method of choice nowadays (see Section 6). 

The methods of peptidic synthesis, in the liquid phase as well as in the solid phase, have led to the preparation of numerous polypeptides that contain a fluorinated amino acid. Most of the examples concern peptidic hormones and neuropeptides, with replacement of either (1) a phenylalanine (or of a tyrosine) by an analogue containing a... 

The effects of the presence of a fluorinated amino acid on the activity of these peptides are changeable the activity can be maintained, enhanced, or lowered the effect can be that of an agonist or antagonist. However, often the biological effect is enhanced, while the affinity is lowered. The loss of affinity is compensated by an increased biodisponibility due to the better hydrolytic and metabolic stability of the polypeptide that contains the fluorinated amino acid. 

The S-ribonuclease is the complex formed between an eicosapeptide and the S-RNAse. While replacement of various amino acids by fluorinated analogues does not modify the activity of the native complex, replacement of His-12 by 4-F-His has a strong influence. Indeed, the S-ribonuclease, formed between the bovine pancreatic S-RNAse and the fluoro peptide that contains 4-F-His, has no more catalytic activity, but it is stable. This loss of enzymatic activity is probably due to the significant lowering of the pAia of the catalytic His (2.5 units), which results from the presence of the fluorine atom. It is known that histidine plays an important role in nucleophilic and acid-base processes, which are connected to the catalytic activity of numerous enzymes. 

In different types of condensed polycyclic systems, mostly nitrogen-containing systems, the elimination of attached fluorine by thiols has proved a valuable synthetic tool for the introduction of sulfur moieties. In 4-(aminosulfonyI)-7-fluoro-2,l,3-benzoxadiazole(l) the reactivity of the fluorine towards sulfur nucleophiles is sufficiently high that it can be used analytically for the detection of thiols14 (c.g., in peptides). The reaction proceeds almost quantitatively. 

Chemical synthesis has provided an additional route to peptides containing halogenat-ed amino acids. Early 19F-NMR studies of proteins were performed on semi-synthetic polypeptides prepared by attachment of fluorinated probes to the polypeptide. For example, Heustis and Raftery modified ribonuclease by trifluoroacetylation of Lys residues 1 and 7. They then used 19F-NMR to study conformational changes brought about by the presence of inhibitors200. In his review, Gerig provides several other examples of this strategy187. 

Meng, H. and Kumar, K. (2007) Antimicrobial activity and protease stability of peptides containing fluorinated amino acids. Journal of the American Chemical Society, 129(50), 15615-15622. 

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