Fluorine, effect acidity

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). 

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 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. 

In this transamination, the effect of para substitient groups has been studied using fluorinated phenylpyruvic acids and L-aspartic acid. From these results, the migratory preference is H > F > Cl > Br > CF3. This order has been attributed to the bulkiness of the substituted group [57]. Direct amination of p-substituted succinic acid with phenylalanine ammonialyase (EC 4.3.1.5) has suggested very high substrate specificity that the order of reaction rate is m-F o-F P-p-F >CF3. 

The effect of fluorination on the reactivity of carbanions has been reviewed.65 66 Fluorination has the same influences on carbanion stability as does the effect of fluorination on acidity (see Section 1.2.). A lot of information has been derived from the effect of fluorination on CH acidity.43 The effect of fluorination on deuterium-hydrogen exchange processes in the case of highly fluorinated substances has been examined with estimates of pKa for highly fluorinaled substrates.67... 

Xenon difluoride [ 3], xenon difluoride complexed with dialkyl sulfides [89], and xenon difluoride intercalated with graphite [90] are all effective reagents for the fluorination of acids, enolates, or enols (Table 2)... 

The preparation of fluorinated pyridine derivatives continues to be of considerable importance due to the effect that the fluorine atom can have on the physical, chemical, and biological properties of the heterocycle. Despite this, there are few reports on the direct electrophilic fluorination of pyridines. The treatment of various quinoline derivatives with elemental fluorine in acidic reaction media afforded mono- and difluorinated products where the halogenation occurred on the benzene ring of the heterocycles <2004JFC661>. 

On the basis of eqn. (45) it would be expected that nitryl fluoride in sulphuric acid is a nitrating agent (besides also possessing fluorinating and sulpho-fluorinating effects). 

Fluorinated amino acids, (VI), and hexynoic derivatives, (VII), prepared by Durley (3) were effective as iNOS inhibitors and used in the treatment of epithelial cell-derived neoplasia. 

Diflunisal is a fluorinated salicyhc acid derivative, which is absorbed unchanged from the gastrointestinal tract, reaching peak concentrations after about 2 hours, and is metabolized by glucuronidation (1). Its adverse effects and other characteristics are those of aspirin, although gastrointestinal haemorrhage may be less common (2). 

Siddiqui, M. A., Driscoll, J. S., Abushanab, E., Kelley, J. A., Batch , J. J., Jr., Marquez, V. E. The" -fluorine effect" in the non-metal hydride radical deoxygenation of fluorine-containing nucleoside xanthates. Nocleosides, Nocleotides Nocleic Acids 2000, 19, 1-12. 

The findings gained with the model system show that two contrary effects characterize the interactions of fluorinated amino acids within the hydrophobic core spatial demand and hydrophobicity on one side, and fluorine-induced polarity on the other. While the increase in hydrophobic surface area upon fluorination may be favorable for hydrophobic interactions, fluorine s inductive effect appears to interfere with the formation of an intact hydrophobic core. In addition, the investigations of fluoroalkyl side-chains in the charged domain as well as the analysis of fluorine s effect on replicase activity indicate that contacts between fluorinated residues may also have an impact on peptide and protein folding. 

The model systems described here deliver useful information about the effect of single fluorinated amino acids on coiled coil folding but, due to the versatility of natural folding motifs, individual proof of structural and thermodynamic effects caused by incorporation of fluorinated amino acids is needed in order to utilize their full potential. 

Salwiczek M., Samsonov S., Vagt T., et al. (2009) Position dependent effects of fluorinated amino acids on hydrophobic core formation of a coiled coil heterodimer. Chemistry - A European Journal (2009) in press. 

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