Trifluoromethylthiolation of tryptophan and tyrosine derivatives : a tool for enhancing the local hydrophobicity of peptides

Gregorc, Jure (author), Lensen, Nathalie (author), Chaume, Grégory (author), Iskra, Jernej (author), Brigaud, Thierry (author)

The incorporation of fluorinated groups into peptides significantly affects their biophysical properties. We report herein the synthesis of Fmoc-protected trifluoromethylthiolated tyrosine (CF$_3$S-Tyr) and tryptophan (CF$_3$S-Trp) analogues on a gram scale (77–93% yield) and demonstrate their use as highly hydrophobic fluorinated building blocks for peptide chemistry. The developed methodology was successfully applied to the late-stage regioselective trifluoromethylthiolation of Trp residues in short peptides (66–80% yield) and the synthesis of various CF$_3$S-analogues of biologically active monoamines. To prove the concept, Fmoc-(CF$_3$S)Tyr and -Trp were incorporated into the endomorphin-1 chain (EM-1) and into model tripeptides by solid-phase peptide synthesis. A remarkable enhancement of the local hydrophobicity of the trifluoromethylthiolated peptides was quantified by the chromatographic hydrophobicity index determination method, demonstrating the high potential of CF$_3$S-containing amino acids for the rational design of bioactive peptides.

• Language: English
• Keywords: aromatic compounds, hydrophobicity, monomers, peptides, proteins, reaction products
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FKKT - Faculty of Chemistry and Chemical Technology
• Publication status: Published
• Publication version: Version of Record
• Year: 2023
• Number of pages: Str. 13169-13177
• Numbering: Vol. 88, iss. 18
• PID: 20.500.12556/RUL-152234
• UDC: 547.1-32-304.2:66.095.253
• ISSN on article: 0022-3263
• DOI: 10.1021/acs.joc.3c01373
• COBISS.SI-ID: 171743491
• Publication date in RUL: 13.11.2023

Record is a part of a journal

• Title: Journal of organic chemistry
• Shortened title: J. org. chem.
• Publisher: American Chemical Society
• ISSN: 0022-3263
• COBISS.SI-ID: 235287

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: aromatske spojine, hidrofobnost, monomeri, peptidi, proteini, reakcijski produkti