Fluorine is the element with the highest electronegativity. Adding fluorine residues decreases the electron density in the adjacent system and increases the polarity of the modified molecule. Thus, the selective fluorination of amino acids at specific positions is a popular strategy to modulate the properties of the resulting peptide, e.g., increased metabolic stability and enhanced lipophilicity.

Especially the trifluoromethylthio group is known for its high lipophilicity (Hansch-Leo parameter: π = 1.44), which is even higher than that of the trifluoromethyl group (π = 0.88), and a strong electron-withdrawing effect (Hammett constants: σ_m = 0.40, σ_p = 0.50).

Besides, addition of a -SCF₃ group to an amino acid increases the local hydrophobicity of the synthetic peptide compared to the unmodified peptide. The diagram below shows the hydrophobicity of H₂N-Ala-X-Leu-OH tripeptides, where X stands for the amino acids Ala, Tyr, and Trp (without modification: blue bar) and their trifluoromethylthiolated analogs (orange bar). See related products at the end of this blog post for the available trifluoromethylthiolated Ala, Tyr, and Trp building blocks.

Hydrophobicity of H₂N-A-X-L-OH tripeptides. X = Ala, Tyr, and Trp. Blue bar: unmodified X. Orange bar: trifluoromethylthiolated X. φ₀ is calculated from the retention time in RP-HPLC.

Thus, the incorporation of a trifluoromethylthio group may lead to a higher membrane permeability (a property which is frequently desired in drug development), as well as to an increased stability of peptides against proteolytic degradation and against oxidation in physiological environments. One further benefit of such an improved pharmacological profile is that the required dosage of a drug may be reduced.

Besides, the introduction of fluorine into peptides and other molecules renders them suitable as probes for protein-protein interactions, which can be measured by ¹⁹F NMR.

→ Interested in all our fluorinated building blocks? Download our flyer! 

→  Looking for other SCF₃ derivatives? Get in contact for a custom synthesis! 

References:

Trifluoromethylthiolation of Tryptophan and Tyrosine Derivatives: A Tool for Enhancing the Local Hydrophobicity of Peptides; J. Gregorc, N. Lensen, G. Chaume, J. Iskra, T. Brigaud; J Org Chem 2023; 88: 13169-13177. https://doi.org/10.1021/acs.joc.3c01373

Probing the Outstanding Local Hydrophobicity Increases in Peptide Sequences Induced by Incorporation of Trifluoromethylated Amino Acids; C. Gadais , E. Devillers, V. Gasparik, E. Chelain, J. Pytkowicz, T. Brigaud; Chembiochem 2018; 19: 1026-1030. https://doi.org/10.1002/cbic.201800088

Trifluoromethyl ethers and -thioethers as tools for medicinal chemistry and drug discovery; G. Landelle, A. Panossian, F. Leroux; Curr Top Med Chem 2014; 14: 941-951. https://doi.org/10.2174/1568026614666140202210016

Selective Fluorination in Drug Design and Development: An Overview of Biochemical Rationales; K. Kirk, Curr Top Med Chem 2006; 6: 1447-1456. https://doi.org/10.2174/156802606777951073

Fluorine in Peptide Design and Protein Engineering; C. Jäckel, B. Koksch; Eur J Org Chem 2005; 21: 4483-4503. https://doi.org/10.1002/ejoc.200500205

Deciphering the Fluorine Code—The Many Hats Fluorine Wears in a Protein Environment; A. Berger, J. Völler, N. Budisa, B. Koksch; Acc Chem Res 2017; 50: 2093-2103. https://doi.org/10.1021/acs.accounts.7b00226

NMR-Solution Structures and Affinities for the Human Somatostatin G-Protein-Coupled Receptors hsst1-5 of CF3 Derivatives of Sandostatin® (Octreotide); D. Seebach, H. Widmer, S. Capone, R. Ernst, T. Bremi, I. Kieltsch, A. Togni, D. Monna, D. Langenegger and D. Hoyer; Helv Chim Acta 2009; 92: 2577-2586. https://doi.org/10.1002/hlca.200900279