Fluorine-containing Amino Acids Research Articles

Establishing Fluorine-Containing Amino Acids as an Orthogonal Tool in Coiled Coil Assembly.

The α-helical coiled coil (CC) is one of the best-characterized folding motifs in the protein world. In this context, fluorinated amino acids have been shown to be capable of tuning the properties of CC assemblies, and especially fluorinated derivatives of aliphatic amino acids can significantly increase the stability of this folding motif when placed in the hydrophobic a and d positions. However, it has not been shown yet whether fluorinated amino acids, by means of rational design, can be used as an orthogonal tool to control CC assembly processes. In the current work, we approached this question by creating a combinatorial peptide library based on a VPE/VPK heteromeric CC system previously established and characterized in our group. This CC model allowed us to screen fluorinated amino acids for interaction with different potential binding partners in position a of the VPE/VPK model with a particular emphasis on studying the impact of stereochemistry within the side chain of α-branched aliphatic fluorinated amino acids on CC properties such as oligomerization state, thermodynamic stability, and orientation. 28 combinations of library members were characterized regarding structure, oligomerization, and thermal stability utilizing circular dichroism, size exclusion chromatography, and Förster resonance energy transfer measurements. This detailed approach showed that the stability and oligomerization state of the motif were not only dependent on the steric demand and the fluorination of corresponding amino acids but also on the stereochemistry within the side chain. The results were applied for a rational design of the fluorine-driven orthogonal assembly, and we could show that CC dimer formation occurred based on specific interactions between fluorinated amino acids. These results demonstrate the potential of fluorinated amino acids as an orthogonal tool besides classical electrostatic and hydrophobic interactions for the fine-tuning and direction of peptide-peptide interactions. Furthermore, within the space of fluorinated amino acids, we could demonstrate the specificity of interactions between differently fluorinated side chains.

Synthesis of Fluorine-Containing Amino Acids from Sulfamidates and Potassium Fluoride

Key words fluorination - potassium fluoride - sulfamidates - fluorpeptides

ChemInform Abstract: Synthesis of Fluorine‐Containing α‐Amino Acids in Enantiomerically Pure Form via Homologation of Ni(II) Complexes of Glycine and Alanine Schiff Bases

AbstractReview: 144 refs.

3-Fluoroaspartate and Pyruvoyl-Dependant Aspartate Decarboxylase: Exploiting the Unique Characteristics of Fluorine To Probe Reactivity and Binding

Fluorine-containing amino acids have been used with great success as mechanism-based inhibitors of pyridoxal phosphate (PLP)-dependent enzymes, and the influence of fluorine on the conformation of molecules has also been extensively studied and practically exploited. In this study, we sought to use these unique characteristics to probe the reactivity and binding of aspartate decarboxylase (ADC) enzymes, which are members of the small class of pyruvoyl-dependant decarboxylases. Since ADC activity has been shown to be essential to the virulence of Mycobacterium tuberculosis, information gained in this manner could be used for the development of inhibitors that selectively target pyruvoyl-dependent enzymes such as ADC, without affecting PLP-dependent enzymes in the host. For this purpose, we synthesized the L-erythro and L-threo isomers of 3-fluoroaspartate and tested their ability to act as substrates and/or inhibitors of the M. tuberculosis and Escherichia coli ADC enzymes. Trapping and MS-based binding analysis was additionally used to confirm that both isomers enter the enzymes' active sites. Our studies show that both isomers undergo single turnover decarboxylation and fluorine elimination reactions to give enamine products that can be trapped within the active site. Interestingly, the enamine/ADC complex that forms from the L-erythro (but not the L-threo) isomer is sufficiently stable that it can be observed even without any trapping. This finding suggests that the two 3-fluoroaspartates maintain different conformations within the ADC active site, which leads to the enamine products with configurations of different stabilities. Taken together, our results provide new insights for the development of cofactor-specific inhibitors, and confirm the utility of fluorine as a unique tool for probing reactivity and binding profiles within enzymes.

Electrochemical activation and carboxylation of fluorine-containing aromatic imines

On the basis of a study of the processes involved in the electrochemical activation of a series of fluorine-containing aromatic imines with and without the presence of carbon dioxide it was shown that the initial stage of such processes is the formation of imine radical-anions, which can both undergo spontaneous transformations and react with CO2 with the formation of fluorine-containing amino acids. A correlation was established between the effects of the electronic structure of the imines on the electrochemical characteristics of their reduction and on the stability of the radical-anions. A relationship was established between the parameters of electrochemical activation of the imines in the presence of CO2 and the yields of the amino acids.

Photoinduced Diastereoselective Addition of Perfluoroalkyl Iodides to Acrylic Acid Derivatives for the Synthesis of Fluorinated Amino Acids

Photoinduced diastereoselective addition of perfluoroalkyl iodides in the presence of an aqueous solution of Na2S2O3 was an excellent method for iodoperfluoroalkylation of acrylic acid derivatives bearing a chiral auxiliary, with moderate to good stereoselectivities and with no detectable side products. The iodoperfluoroalkylation of N-acyloylcamphorsultam provided a convenient route for preparing chiral fluorine-containing amino acids.

Transition metal-catalyzed formation of CF 3-substituted α,β-unsaturated alkene and the synthesis of α-trifluoromethyl substituted β-amino ester

A new transition metal-catalyzed formation of CF 3-substituted α,β-unsaturated alkenes through the ylide intermediate from the reaction between methyl 3,3,3-trifluoro-2-diazopropionate 1 and aryl aldehydes has been developed. Further transformation of the alkene affords the α-trifluoromethyl substituted β-amino ester, a valuable intermediate in the synthesis of fluorine-containing amino acids with potential biological application.

Synthesis of Fluorine‐Containing Bioisosteres Corresponding to Phosphoamino Acids and Dipeptide Units

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of fluorine-containing bioisosteres corresponding to phosphoamino acids and dipeptide units.

It has been shown that fluorinated analogues of naturally occurring biological active compounds including amino acids often exhibit unique physiological activity. Among wide varieties of fluorine-containing amino acids, nonhydrolyzable phosphoamino acids possessing a substituent of the difluoromethylene (CF(2)) unit for the phosphoryl ester oxygen are of value in the medicinal and biological fields. We have engaged in the synthesis of these classes of nonhydrolyzable phosphoamino acids corresponding to pTyr 3, pSer 4, and pThr 5 with their incorporation into peptides using newly developed deprotecting procedures. In this article, stereoselective synthesis of the CF(2)-substituted pThr mimetics and development of a two-step deprotecting methodology for the nonhydrolyzable analogues are reviewed. In the course of the above synthetic study, we found that gamma,gamma-difluoro-alpha,beta-enoates were reduced to gamma-fluoro-beta,gamma-enoates by organocopper reagents and then applied to the synthesis of (Z)-fluoroalkene dipeptide isosteres, which have served as potential dipeptide mimetics having structural as well as electrostatic similarity to the parent peptide bonds. Furthermore, mechanistic investigation of the organocopper-mediated reduction led us to development of a SmI(2)-mediated approach toward the synthesis of the fluoroalkene isosteres.

ChemInform Abstract: Preparation of Fluorine‐Containing Amino Acids by Methods of Organofluorine Chemistry

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Fluorine-containing amino acids

This mini-review covers Ukrainian studies on the synthesis of chiral fluorine-containing amino acids by catalytic reduction, perfluoroalkylation of hydroxy-containing amino acids and enzymatic resolution of racemic mixtures of fluorine-containing amino acids.

General method for the asymmetric synthesis of fluorine-containing amino acids

Several recent developments in our laboratories have made it possible to elaborate a general method for preparing optically pure fluorine containing α-amino acids starting from a Ni(II)-complex ( 1) of a Schiff's base derived from (S)-o-[(benzylpropyl)amino]-benzophenone (BBP) and glycine or alanine. ▪ Alkylation of ( 1) with fluorine-substituted benzyl halides and aldehyde condensation result, respectively, in fluorine-containing S-Phe and its α-methyl derivatives, 2R,3S-, 2S,3R-, 2R,3R-PhSer and 2S,3S-β-perfluoroalkyl Ser in good chemical and optical yields. Simplicity of the synthetic procedure, ease of recovery of the chiral auxiliary (BBP), and the possibility of obtaining optically pure fluorine containing amino acids make this method attractive. The influence of fluorine atoms or fluorine containing groups and reaction conditions on the stereochemical results in the reactions of this type will be discussed.

Synthesis of fluorine-containing amino acids

Synthesis of fluorine-containing amino acids

Fluorine-containing amino acids and their derivatives. 9. Synthesis and biological activities of difluoromethylhomocysteine

A new fluorine-containing amino acid, difluoromethylhomocystein, was prepared in a chiral form. Some of its biological activities are described.

ChemInform Abstract: Enzymatic Synthesis of Fluorine‐Containing Amino Acids

Some amino acids are synthesized effectively by enzymatic reactions. These enzymatic reactions are also applicable to the synthesis of optically active fluorine-containing amino acids by the use of corresponding fluorine-containing precursors.This paper describes the following enzymatic reactions. 1) Synthesis of fluorine-containing phenylalanines by transamination of corresponding fluorine-containing phenylpyruvic acids, by phenylalanine ammonia-lyase reaction of fluorine-containing t-cinnamic acids, and by acylase reaction of fluorine-containing N-acetyl phenylalanines, 2) synthesis of fluorotyrosines by β-tyrosinase starting from fluorophenols and serine, 3) synthesis of fluorotryptophan by tryptophanase starting from fluoroindole and serine.

Fluorine-containing amino acids. IV. Synthesis and biological activity of β-polyfluoromethyl-substituted aromatic amino acids

Fluorine-containing amino acids. IV. Synthesis and biological activity of β-polyfluoromethyl-substituted aromatic amino acids

含フッ素アミノ酸の酵素合成

Some amino acids are synthesized effectively by enzymatic reactions. These enzymatic reactions are also applicable to the synthesis of optically active fluorine-containing amino acids by the use of corresponding fluorine-containing precursors.This paper describes the following enzymatic reactions. 1) Synthesis of fluorine-containing phenylalanines by transamination of corresponding fluorine-containing phenylpyruvic acids, by phenylalanine ammonia-lyase reaction of fluorine-containing t-cinnamic acids, and by acylase reaction of fluorine-containing N-acetyl phenylalanines, 2) synthesis of fluorotyrosines by β-tyrosinase starting from fluorophenols and serine, 3) synthesis of fluorotryptophan by tryptophanase starting from fluoroindole and serine.

Fluorine-containing amino acids and their derivatives. 4. Synthesis and antibacterial activity of threo and erythro 1-fluorodehydroxylated chloramphenicol analogues.

Both threo and erythro 1-fluorodehydroxylated chloramphenicol analogues were synthesized and tested for antimicrobial activity. None showed antibacterial or antifungal activity, clearly demonstrating that substitution of the secondary hydroxyl group with fluorine abolishes the antibacterial activity of the parent compound, chloramphenicol. This finding sharply contrasts with that of previous workers, in which fluorination of the 3-hydroxyl group enhanced antibacterial activity against many chloramphenicol-resistant strains.

Fluorine-containing amino acids and their derivatives. 6. An efficient synthesis of β-fluorinated alanines via fluorohalomethylation of aminomalonates

Aminomalonates, e.g., 1 and 2 , smoothly reacted with difluoro- and chlorofluorocarbene to produce the adducts ( 3 , 4 , and 5 ) in good yields. These products were successfully converted to various versatile β-fluorinated alanine derivatives, i.e., β,β-difluoroalanine ( 6 ), N-acyl-β-fluorodehydroalaninate ( 7 ), and fluoropyruvic acid ( 8 ).

Fluorine-containing Amino Acids and Their Derivatives. 5. Synthesis of Novel Fluorinated Analogues of the Antitumor Agent, Methotrexate

Fluorine-containing Amino Acids and Their Derivatives. 5. Synthesis of Novel Fluorinated Analogues of the Antitumor Agent, Methotrexate