Ionic Liquid-Mediated Approach for the Synthesis of Site-Specific Thioether Conjugates — ASN Events

Ionic Liquid-Mediated Approach for the Synthesis of Site-Specific Thioether Conjugates (#204)

Helal Abujubara 1 , Jie Dr Yang 1 , A. Birsen Otyakmaz 1 , Anaïs Dr Noisier 2 , Werngard Dr Czechtizky, 2 , Malin Dr Lemurell 2 , Alesia Dr Tietze 1
  1. Gothenburg University, Gothenburg, Sweden
  2. AstraZeneca, Gothenburg, Sweden

In recent years bioconjugation methodologies have become a central part of therapeutic development, notably for the synthesis of biochemical probes or molecular conjugates for targeted delivery. While originally employed in oncology to improve the therapeutic index of chemotherapeutic drugs, conjugates are now being leveraged for the targeted delivery of potent molecules within a wide range of therapeutic areas.

Herein, for the first time, we report that ionic liquid (IL) can be used for the conjugation reaction. This IL-mediated thiolation methodology includes the site-selective modification of peptides with moieties to improve their physicochemical properties, the synthesis of biochemical probes (e.g. localization of drug targets in vivo or visualization of cell compartments) or molecular conjugates (e.g. peptide drug conjugates). The method relies on the use of 1,3- ethyl-methyl imidazolium acetate, [C2mim][OAc] as a reagent and precursor to generate activated IL, as well as a solvent for the conjugation reaction. First, a focused library of active ILs was synthesized to functionalize/conjugate cysteine-containing small molecules and unprotected peptides. Interestingly, a bifunctional active IL could also be successfully employed as a linker for the conjugation of peptides lacking Cys. This reaction occurs under mild conditions and preserves the stereochemical integrity of the substrate.648c7b5cb3f28-Figure1.bmp

Ionic-liquid-driven conjugation to thiol-containing biomolecules. This method is based on the generation of “active ILs” with various functionalities (R) as a toolbox which then is reacted with a thiol-containing biomolecule to form thioethers. In principle, the biomolecule (blue helix) could be a peptide, an antibody, a protein, or a thiol-modified oligonucleotide, A = anion, which is either iodide or bromide.

This pioneering and initial study is a starting point to study the IL-mediated thiolation of larger and more complex biomolecules.

  1. Abujubara, H., Yang, J., Otyakmaz, B., Noisier, A. F. M., Czechtizky, W., Lemurell, M. and Tietze, A. A.,* Ionic liquid-mediated approach for the synthesis of site-specific thioether conjugates (2023), Chem. Eur. J., e202203915, DOI: 10.1002/chem.202203915
#AusPeptide2023