Fluorinated amino acids

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Fluorinated amino acids

(R)-N-FMOC-a-methyl-2-fluorophenylalanine

CAS 193086-74-7
Catalog BAT-014121
Molecular Weight 419.45
Molecular Formula C25H22FNO4
(R)-N-FMOC-a-methyl-2-fluorophenylalanine

(2R,3R)-3-Amino-3-(4-fluoro-phenyl)-2-hydroxy-propionic acid

CAS 55652-55-6
Catalog BAT-014126
Molecular Weight 199.18
Molecular Formula C9H10FNO3
(2R,3R)-3-Amino-3-(4-fluoro-phenyl)-2-hydroxy-propionic acid

Fmoc-(S)-3-Amino-4-(4-trifluoromethyl-phenyl)-butyric acid

CAS 270065-81-8
Catalog BAT-014139
Molecular Weight 469.45
Molecular Formula C26H22F3NO4
Fmoc-(S)-3-Amino-4-(4-trifluoromethyl-phenyl)-butyric acid

(R)-alpha-(4-fluoro-benzyl)-proline

CAS 637020-68-9
Catalog BAT-014154
Molecular Weight 223.24
Molecular Formula C12H14FNO2
(R)-alpha-(4-fluoro-benzyl)-proline

(S)-alpha-(4-fluoro-benzyl)-proline

CAS 637020-70-3
Catalog BAT-014155
Molecular Weight 223.24
Molecular Formula C12H14FNO2
(S)-alpha-(4-fluoro-benzyl)-proline

(R)-3-Amino-4-(pentafluoro-phenyl)-butyric acid

CAS 269398-92-7
Catalog BAT-014171
Molecular Weight 269.17
Molecular Formula C10H8F5NO2
(R)-3-Amino-4-(pentafluoro-phenyl)-butyric acid

(R)-3-Amino-4-(3,4-difluoro-phenyl)-butyric acid

CAS 269396-58-9
Catalog BAT-014174
Molecular Weight 215.20
Molecular Formula C10H11F2NO2
(R)-3-Amino-4-(3,4-difluoro-phenyl)-butyric acid

(bR)-b-Amino-2-(trifluoromethyl)benzenebutanoic acid

CAS 269396-76-1
Catalog BAT-014178
Molecular Weight 247.21
Molecular Formula C11H12F3NO2
(bR)-b-Amino-2-(trifluoromethyl)benzenebutanoic acid

(bR)-b-Amino-3-(trifluoromethyl)benzenebutanoic acid

CAS 269726-73-0
Catalog BAT-014179
Molecular Weight 247.21
Molecular Formula C11H12F3NO2
(bR)-b-Amino-3-(trifluoromethyl)benzenebutanoic acid

4-Trifluoromethyl-D-β-homophenylalanine hydrochloride

CAS 269726-76-3
Catalog BAT-014180
Molecular Weight 247.21
Molecular Formula C11H12F3NO2
4-Trifluoromethyl-D-β-homophenylalanine hydrochloride

(S)-3-Amino-4-(2-fluoro-phenyl)-butyric acid

CAS 246876-92-6
Catalog BAT-014189
Molecular Weight 197.21
Molecular Formula C10H12FNO2
(S)-3-Amino-4-(2-fluoro-phenyl)-butyric acid

(S)-3-Amino-4-(3-fluoro-phenyl)-butyric acid

CAS 270596-50-4
Catalog BAT-014191
Molecular Weight 197.21
Molecular Formula C10H12FNO2
(S)-3-Amino-4-(3-fluoro-phenyl)-butyric acid

(S)-3-Amino-4-(4-fluoro-phenyl)-butyric acid

CAS 270596-53-7
Catalog BAT-014192
Molecular Weight 197.21
Molecular Formula C10H12FNO2
(S)-3-Amino-4-(4-fluoro-phenyl)-butyric acid

(S)-3-amino-4-(pentafluoro-phenyl)-butyric acid

CAS 270063-41-7
Catalog BAT-014200
Molecular Weight 269.17
Molecular Formula C10H8F5NO2
(S)-3-amino-4-(pentafluoro-phenyl)-butyric acid

(S)-3-Amino-4-(3,4-difluoro-phenyl)-butyric acid

CAS 270063-53-1
Catalog BAT-014205
Molecular Weight 215.20
Molecular Formula C10H11F2NO2
(S)-3-Amino-4-(3,4-difluoro-phenyl)-butyric acid

(S)-3-Amino-4-(2-trifluoromethyl-phenyl)-butyric acid

CAS 270065-73-1
Catalog BAT-014209
Molecular Weight 247.21
Molecular Formula C11H12F3NO2
(S)-3-Amino-4-(2-trifluoromethyl-phenyl)-butyric acid

(S)-3-Amino-4-(3-trifluoromethyl-phenyl)-butyric acid

CAS 270065-76-4
Catalog BAT-014210
Molecular Weight 247.21
Molecular Formula C11H12F3NO2
(S)-3-Amino-4-(3-trifluoromethyl-phenyl)-butyric acid

(S)-3-Amino-4-(4-trifluoromethyl-phenyl)-butyric acid

CAS 270065-79-7
Catalog BAT-014211
Molecular Weight 247.21
Molecular Formula C11H12F3NO2
(S)-3-Amino-4-(4-trifluoromethyl-phenyl)-butyric acid

(S)-2-(tert-Butoxycarbonylamino)-4,4-difluorobutanoic acid

CAS 467442-20-2
Catalog BAT-014231
Molecular Weight 239.22
Molecular Formula C9H15F2NO4
(S)-2-(tert-Butoxycarbonylamino)-4,4-difluorobutanoic acid

Ethyl 3-(Boc-amino)-2,2-difluoropropanoate

CAS 847986-13-4
Catalog BAT-016015
Molecular Weight 253.24
Molecular Formula C10H17F2NO4
Ethyl 3-(Boc-amino)-2,2-difluoropropanoate

Introduction

Fluorine is one of the most abundant elements on earth, yet it occurs extremely rarely in biological compounds. Most of the fluorine is in the form of insoluble fluoride minerals, and consequently, the concentration of free fluoride in sea and surface water is very low. Interestingly, the replacement of hydrogen with fluorine in organic compounds is often accompanied by profound and unexpected changes in biological activity. In recent years, many methods have been developed for the synthesis of fluorinated amino acids and their derivatives. There are two main methods for synthesizing fluorinated amino acids: direct fluorination and fluorinated block method. Direct fluorination means the introduction of fluorine atoms or fluorine-containing groups in the molecule through electrophilic or nucleophilic fluorination reagents. However, these fluorinated reagents tend to react more vigorously in the application process, which is difficult to control, poor selectivity, and difficult to meet the requirements of organic synthesis, so their application is greatly limited. Among them, fluorinated block method does not involve the formation and fracture of C-F bond, so it has the advantages of mild reaction conditions and good selectivity. 2-Bromo-3, 3, 3-trifluoropropylene (BTP) is an easily available and widely used fluorinated block, which can be used in various coupling and addition reactions. By introducing the block into the amino acid, the intermediate obtained contains the double bond of carbon and carbon, and a variety of fluorine-containing amino acids can be synthesized by a simple transformation. The introduction of trifluoromethyl into amino acids can increase the fat-solubility of amino acids. At the same time, the strong bond energy of the C-F bond makes trifluoromethyl have strong stability, thus increasing the stability of amino acids.

Application

Protein: Recent studies with fluorinated amino acids suggest new opportunities for the construction of hyper stable protein folds and directing highly specific protein-protein interfaces, and are some of the most successful and potentially general of the studies with unnatural amino acids. there have been numerous studies aimed at using extensively fluorinated (or fluorous) amino acids to modulate the properties of proteins and particularly, increase their thermal stability fluorous analogs of hydrophobic amino acids such as leucine, valine, and phenylalanine have been incorporated into both natural and de novo-designed proteins either biosynthetically or by chemical synthesis. Proteins with sequences containing up to ∼25% fluorous residues have been synthesized without gross structural perturbation. In almost all cases, fluorination significantly enhances stability to thermal unfolding, chemical denaturation, and proteolytic degradation, with minimal impact on the biological activity of the protein or peptide.

Polypeptide: Polypeptide drugs generally contain a few to dozens of amino acids, and their molecular weights are between small molecules and protein-based drugs. The stability of polypeptide drugs is poor, its stability is easily affected by temperature, pH, etc., easy to degrade in vivo, short half-life. Some polypeptide drugs have large molecular weight and poor lipid solubility, which make it difficult to pass through biofilms. Therefore, polypeptide drugs cannot be taken orally, which has become an important factor restricting the development of poly polypeptide drugs. Amino acids are the basic constituent units of polypeptides. It is an important way to improve the biological activity of poly polypeptides by changing the amino acid fragments in polypeptides and then changing the conformation of polypeptides. For example, when hydrophobic fluorine-containing amino acids are introduced into the hydrophobic center of the polypeptide, the structural characteristics and chemical characteristics of the polypeptide can be changed, the thermal stability and chemical stability can be improved, and the lipid solubility can be improved, to improve its activity in the organism. Besides, the replacement of natural amino acids in some peptide chains with fluorine-containing amino acids can significantly increase the specific protein-ligand or protein-protein interactions, thereby improving the proteolysis and thermal stability of polypeptides and improving the therapeutic effect.

Pharmaceutical chemistry: Fluorinated molecules also have important medical applications, exemplified by 20% of all pharmaceuticals containing fluorine, which improves pharmacokinetic properties. Interest in fluorinated amino acids dates back to the mid-1950s when J. Fried and J. Sabo developed the first fluorine-containing drug fludrocortisone, convincingly demonstrating that the introduction of fluorine can be used to improve the biological properties of naturally occurring compounds. Fluoro-containing amino acids have been used as antiviral and anti-tumor agents, and the combination of fluoro-containing amino acids and proteins can enhance the activity of proteins. Peptides or proteins contain these valuable structural motifs, which can be used as probes to study enzyme kinetics and protein interactions, and even as PET imaging agents.

References

  1. BUER B C, MEAGHER J L, STUCKEY J A, et al. Structural Basis for the Enhanced Stability of Highly Fluorinated Proteins[J]. Proceedings of the National Academy of Sciences, 2012, 109(13): 4810–4815. DOI:10.1073/pnas.1120112109.
  2. SALWICZEK M, NYAKATURA E K, GERLING U I M, et al. Fluorinated Amino Acids: Compatibility with Native Protein Structures and Effects on Protein–Protein Interactions[J]. Chem. Soc. Rev., 2012, 41(6): 2135–2171. DOI:10.1039/C1CS15241F.

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