Fluoroalanine

Last updated
Fluoroalanine
3-Fluoroalanine.png
Names
IUPAC name
(2S)-2-amino-3-fluoropropanoic acid
Other names
β-fluoroalanine
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.047.810 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C3H6FNO2/c4-1-2(5)3(6)7/h2H,1,5H2,(H,6,7)/t2-/m1/s1 Yes check.svgY
    Key: UYTSRQMXRROFPU-UWTATZPHSA-N Yes check.svgY
  • C([C@H](C(=O)O)N)F
Properties
C3H6FNO2
Molar mass 107.084 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Fluoroalanine, specifically 3-fluoro-alanine, is a fluorinated analogue of the amino acid alanine. Historically considered as an antibiotic, it also has potential applications as a radioactive tracer in positron emission tomography (PET). [1]

Contents

Synthesis

The first reported syntheses of fluoroalanine in 1976 involved treating cysteine with difluorine under an inert atmosphere. This produced a mixture of 3-fluoroalanine and 3,3-difluoroalanine, with the former as the major component. [2]

Fluoroalanine synthesis.png

3-Fluoroalanine, 3,3-difluoroalanine, and 3,3,3-trifluoroalanine can also be synthesised by treating alanine directly with UV-irradiated trifluoromethyl hypofluorite. [2]

Optically pure 3-fluoroalanines can be produced through an oxazolidinone intermediate that can be obtained from L- or D-serine. [3] Enzymatic synthesis of alanine with varying degrees of fluorination has been reported, using substrates such as 3-fluoropyruvate and a serine-derivatised sulfamidate. [4] [5]

Applications

3-Fluoroalanine produced using the radioactive 18F isotope has potential applications in Positron Emission Tomography as a radioactive tracer. The D-enantiomer has shown promise in differentiating between bacterial infection and sterile inflammation. [1] A deuterated L-enantiomer expressed enhanced tumour uptake, warranting further biological investigation into its use as a cancer imaging agent. [5]

3-Fluoroalanine is described as unstable and generally unsuitable for peptide synthesis. Under basic conditions, it is prone to dehydrofluorination, and the proximity of the fluorine substituent to the amine group reduces the nucleophilicity of the latter. However, it has been successfully used in developing analogues to the immunosuppressant Cyclosporin A. Additionally, dehydrofluorination of 3-fluoroalanine produces a double-bond, providing a route for further amino acid functionalisation. [6] In 2015, the synthesis of N-Fmoc-protected 3-fluoroalanine grants viable routes towards incorporating fluorinated alanine probes within synthetic peptides. [7]

While fluoroalanine may refer to various isomers of 3-fluoroalanine, other functional analogues and isotopologues are of note.

Isomers

Functional analogues and derivatives

Isotopologues

References

  1. 1 2 Li, Kaixuan; Tolentino Collado, Jinnette; Marden, Jocelyn A.; Pollard, Alyssa C.; Guo, Shuwen; Tonge, Peter J.; Qu, Wenchao (2024-08-22). "Biological Evaluation of d-[18F]Fluoroalanine and d-[18F]Fluoroalanine-d3 as Positron Emission Tomography Imaging Tracers for Bacterial Infection". Journal of Medicinal Chemistry. 67 (16): 13975–13984. doi:10.1021/acs.jmedchem.4c00783. ISSN   0022-2623. PMC   11342404 . PMID   39082959.
  2. 1 2 Tolman, V. (1996-03-01). "Syntheses of fluorinated amino acids: from the classical to the modern concept". Amino Acids. 11 (1): 15–36. doi:10.1007/BF00805718. ISSN   1438-2199.
  3. ↑ Hoveyda, Hamid R.; Pinault, Jean-François (2006-12-01). "(2 R )- and (2 S )-3-Fluoroalanine and Their N -Methyl Derivatives: Synthesis and Incorporation in Peptide Scaffolds". Organic Letters. 8 (25): 5849–5852. doi:10.1021/ol062434q. ISSN   1523-7060.
  4. ↑ Nieto-Domínguez, Manuel; Sako, Aboubakar; Enemark-Rasmussen, Kasper; Gotfredsen, Charlotte Held; Rago, Daniela; Nikel, Pablo I. (2024-05-09). "Enzymatic synthesis of mono- and trifluorinated alanine enantiomers expands the scope of fluorine biocatalysis". Communications Chemistry. 7 (1): 104. doi:10.1038/s42004-024-01188-1. ISSN   2399-3669.
  5. 1 2 Li, Kaixuan; Gilberti, Alexa L.; Marden, Jocelyn A.; Akula, Hari K.; Pollard, Alyssa C.; Guo, Shuwen; Hu, Bao; Tonge, Peter J.; Qu, Wenchao (2024-06-27). "Synthesis and Biological Evaluation of Fluorine-18 and Deuterium Labeled l-Fluoroalanines as Positron Emission Tomography Imaging Agents for Cancer Detection". Journal of Medicinal Chemistry. 67 (12): 10293–10305. doi:10.1021/acs.jmedchem.4c00774. ISSN   0022-2623. PMC   11258582 . PMID   38838188.
  6. ↑ Salwiczek, Mario; Nyakatura, Elisabeth K.; Gerling, Ulla I. M.; Ye, Shijie; Koksch, Beate (2012). "Fluorinated amino acids: compatibility with native protein structures and effects on protein–protein interactions". Chem. Soc. Rev. 41 (6): 2135–2171. doi:10.1039/C1CS15241F. ISSN   0306-0012.
  7. ↑ Carpentier, Claudia; Godbout, Raphaël; Otis, François; Voyer, Normand (2015-03-04). "Synthesis and use of N-Fmoc-l-fluoroalanine". Tetrahedron Letters. 56 (10): 1244–1246. doi:10.1016/j.tetlet.2015.01.117. ISSN   0040-4039.
  8. ↑ Johnson, Martin R.; Barnes, Stephen; Sweeny, David J.; Diasio, Robert B. (1990). "2-Fluoro-β-alanine, a previously unrecognized substrate for bile acid coenzyme A:Amino acid:N-acyltransferase from human liver". Biochemical Pharmacology. 40 (6): 1241–1246. doi:10.1016/0006-2952(90)90389-3.
  9. ↑ Boutahri, Yazid; Ben Haj Salah, Khoubaib; Tisserand, Nicolas; Lensen, Nathalie; Crousse, Benoît; Brigaud, Thierry (2023-09-22). "Difluoroalanine: Synthesis, Incorporation in Peptides, and Hydrophobic Contribution Assessment". Organic Letters. 25 (37): 6937–6941. doi:10.1021/acs.orglett.3c02853. ISSN   1523-7060.
  10. ↑ Wang, Elizabeth A.; Walsh, Christopher (1981-12-01). "Characteristics of .beta.,.beta.-difluoroalanine and .beta.,.beta.,.beta.-trifluoroalanine as suicide substrates for E. coli B alanine racemase". Biochemistry. 20 (26): 7539–7546. doi:10.1021/bi00529a032. ISSN   0006-2960.
  11. ↑ Höss, E.; Sewald, N.; Gaa, K.; Burger, K. (1989-10-01). "New efficient syntheses for 3.3.3-trifluoroalanine, 2-deutero-3.3.3-trifluoroalanine and their N-protected derivatives". Journal of Fluorine Chemistry. 45 (1): 165. doi:10.1016/S0022-1139(00)84537-6. ISSN   0022-1139.
  12. ↑ Dessipri, E.; Tirrell, D. A. (1994). "Trifluoroalanine N-Carboxy Anhydride: A Reactive Intermediate for the Synthesis of Low Surface Energy Polypeptides". Macromolecules. 27 (19): 5463–5470. doi:10.1021/ma00097a028. ISSN   0024-9297.
  13. ↑ Cordes, Eugene H. (2020-09-17), "Fludalanine: nice try but no hallelujah", Hallelujah Moments (2 ed.), Oxford University PressNew York, pp. 139–152, doi:10.1093/oso/9780190080457.003.0009, ISBN   978-0-19-008045-7 , retrieved 2026-01-12
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.