Fluorinated amino acids
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Fluorinated amino acids

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BOC Sciences brings to its customers a wide range of fluorinated amino acids that are used in the fields of protein engineering, imaging, and medicinal chemistry.

What are Fluorinated Amino Acids?

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. Interestingly, the replacement of hydrogen with fluorine in organic compounds is often accompanied by profound and unexpected changes in biological activity. Fluorinated amino acids refer to compounds that introduce fluorine atoms into amino acids. The introduction of fluorine atoms enhances the stability of the molecule, regulates the folding and conformation of proteins, and alters the pharmacokinetic properties of the molecule.

Types of Fluorinated Amino Acids

  • α-Fluorinated Amino Acids

Alpha-fluorinated amino acids refer to derivatives that introduce a fluorine atom on the alpha-carbon of the amino acid. This type of fluorinated amino acids includes α-fluoroproline, α-fluoroisoleucine, etc.

  • Side-chain Fluorinated Amino Acids

Side-chain fluorinated amino acids refer to derivatives that introduce fluorine atoms into the side chains of amino acids. Common examples include: fluorophenylalanine, trifluorophenylalanine, etc.

  • Polyfluorinated Amino Acids

Polyfluorinated amino acids are compounds that introduce multiple fluorine atoms into an amino acid. Common examples include: difluorophenylalanine, trifluoroproline, and others.

Types of fluorinated amino acids.Fig.1 Types of fluorinated amino acids. (Cho et al., 2014)

Synthesis of Fluorinated Amino Acids

There are two main methods for synthesizing fluorinated amino acids: direct fluorination and fluorinated block method.

  • Direct Fluorination

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.

  • Fluorinated Block Method

This 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.

Applications of Fluorinated Amino Acids

  • Protein Engineering

By introducing fluorinated amino acids into protein sequences, it is possible to modulate protein folding, stability, and function, protein interactions with ligands or other proteins, and enhance protein resistance to enzymatic degradation. 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.

  • Pharmaceutical Chemistry

The development of the first fluoride-containing drug, fludrocortisone, in the mid-1950s provided convincing evidence that the introduction of fluorine could be used to improve the biological properties of natural 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.

  • Chemical Biology Study and Imaging

By introducing fluorinated amino acids, proteins or peptides can be labeled, allowing for their tracking and localization in organisms. Fluorinated amino acids can also be used to study the structure, function and interactions of proteins, as well as to develop bioactive molecules with specific functions. Fluorinated amino acids are commonly used in radiolabeling and imaging applications due to the radioactive properties and imaging capabilities of the fluorine-18 isotope. For example, fluorinated amino acids can be combined with fluorine-18 isotopes to prepare radiolabeled substances such as fluorine-18 fluorodeoxyglucose (FDG) for tumor diagnosis and molecular imaging studies.

Reference

  1. Cho J, et al. Stabilization of β-peptide helices by direct attachment of trifluoromethyl groups to peptide backbones[J]. Chemical Communications, 2014, 50(69): 9855-9858.
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