Fluorinated Amino Acids

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Fluorine is an electron isostere of hydrogen and has special properties, such as small atomic radius, large electronegativity, and strong electron attraction. In medicinal chemistry, the introduction of fluorine or fluorinated groups (such as trifluoromethyl or trifluoromethylpiperidine groups) can lead to changes in the activity, selectivity, and pharmacokinetics (ADME) properties of the parent molecule. BOC Sciences is a leading supplier of high-quality fluorinated amino acids, offering a broad range of products to meet the needs of researchers and pharmaceutical companies worldwide. With an unwavering commitment to quality and customer satisfaction, BOC Sciences has become a trusted partner in chemical supply. Whether you are conducting research in the laboratory or developing new pharmaceutical products, BOC Sciences can provide the high-quality fluorinated amino acids you need to achieve your goals.

What is Fluorinated Amino Acid?

Fluorinated amino acids (FAA) are a class of amino acids with special biological activity and potential medicinal value. They are divided into fluorinated alfa amino acids (F-aAAs), fluorinated b-amino acids (F-bAAs), and fluorinated cyclic amino acids (F-CAAs). Due to their strong hydrophobicity, the introduction of fluorinated amino acids and their derivatives into peptide drugs can usually improve the thermal and chemical stability of the drug, increase the lipid solubility, thereby greatly improving the biological and pharmacological activity. So far, only one fluorine-containing amino acid has been found in nature, namely 4-fluoro-L-threonine (4F-Thr). It is a fluorine-containing amino acid produced by Streptomyces cattleya and has broad-spectrum antibacterial activity. In recent decades, the synthesis of fluorine-containing amino acids has received increasing attention from medicinal chemists in the field of drug research and is an important building block in the synthesis of drugs.

Fluorinated Amino Acid Types

• Complex Fluorine-Containing Aromatic Amino Acids

Because of their wide range of targetable activities and substitution patterns, synthetic investigations on unnatural amino acids with aromatic rings have been conducted. Applications for aromatic residues added to peptides and proteins are numerous and include fluorescence, tagging, and quantitative analysis. Because fluorinated aromatic amino acids are easily monitored by F NMR, they are useful tools for investigating biosynthetic routes. Fluorinated aromatic amino acids have been demonstrated to significantly change the spectral characteristics of peptides as well as their tendency to form helices, interact with other proteins, and change the solubility of the peptides. Complex fluorinated aromatic amino acids usually include the following categories:

• Aromatic amino acids
• Quaternary aromatic fluorinated amino acids
• Heterocyclic fluorinated amino acids
• Spirocyclic fluorinated amino acids

• Complex Fluorine-Containing Non-Aromatic Amino Acids

Most naturally occurring amino acids are nonaromatic. For this reason, a large amount of research has been aimed at developing access to novel aliphatic amino acids. The incorporation of unnatural aliphatic amino acids into peptides and proteins has been shown to modulate a range of physical and chemical properties. In this area, the ability to introduce fluorinated moieties has attracted considerable attention. Compound fluorinated non-aromatic amino acids usually include the following categories:

• Cyclic non-aromatic fluorinated amino acids
• Acyclic fluorinated non-aromatic amino acids
• SFx amino acids

In addition, according to the structure and the number of fluorine atoms, fluorinated amino acids can also be divided into α-fluorinated amino acids, side chain fluorinated amino acids and polyfluorinated amino acids.

• α-Fluorinated amino acids refer to derivatives in which fluorine atoms are introduced into the α-carbon of amino acids. Such fluorinated amino acids include α-fluoroproline, α-fluoroisoleucine, etc.
• Side chain fluorinated amino acids refer to derivatives in which fluorine atoms are introduced into the side chains of amino acids. Common examples include: fluorophenylalanine, trifluorophenylalanine, etc.
• Polyfluorinated amino acids are compounds in which multiple fluorine atoms are introduced into amino acids. Common examples include: difluorophenylalanine, trifluoroproline, etc.

Fluorinated Amino Acid Synthesis

The synthesis of fluorinated amino acids is a rather complex field. Due to the particularity of the fluorine element, there is currently no general method for introducing fluorine substituents into amino acids. Instead, a suitable synthetic route needs to be chosen based on the number of fluorine substituents, their position in the side chain, and possible further functionality. These factors not only affect the structural properties of the target amino acid, but also affect the reactivity of all functional groups and the acidity of adjacent substituents, thereby affecting the stereochemical properties of the amino acid. Currently, the synthesis of fluorinated amino acids is mainly divided into two strategies:

• Introduction of functional groups - the introduction of amino groups and carboxylic acids into fluorine-containing compounds, and the introduction of fluorine-containing groups into amino acids;
• Fluorination reaction of side chains - converting hydroxyl groups, aldehyde groups, double bonds and other groups into fluorine-containing groups (Fig. 1).

Fig. 1. Synthesis of fluorinated α-amino acids.

In fluorination reactions, common fluorination reagents include nucleophilic fluorination reagents, electrophilic fluorination reagents, free radical fluorination reagents and trifluoromethylating reagents (Fig. 2). The development of fluorination reagents and the innovation of fluorination reaction methods have led to rapid development of fluorine chemistry and provided more selectivity for medicinal chemistry.

Fig. 2. Common fluorinating reagents.

Applications of Fluorine-Containing 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.