TFA Cleavage Strategy for Mitigation of S-tButylated Cys-Peptide Formation in Solid-Phase Peptide Synthesis

• DOI: 10.1021/acs.oprd.4c00443
• Publication Date: 2025-02-23T14:51:31Z
• Authors: Sinenhlanhla N. M...; Amit Chakraborty; Ralph Schönleber; Fernando Albericio; Beatriz G. de la ...
• Keywords: Peptide Synthesis; Cleavage (geology); Solid-Phase Synthesis

Cysteine (Cys) is the most versatile amino acid-forming part of a peptide chain but at same time complex. Its presence associated with large number side reactions. In particular, formation S-tert-butylated Cys residues results from reaction liberated thiol tBu cations coming tBu-based protecting groups. Here, we have studied this using different scavengers such as alkyl and aryl thiols (DTT, 1,4-BDMT), thioethers (DMS, thioanisole), sulfur-free compounds m-cresol, anisole, PPh3 TCEP in addition to TIS H2O. Three these 1,4-BDMT, PPh3) are disulfide-reducing agents. Furthermore, study also considered cleavage duration TFA content mixtures. peptides containing Ser(tBu) and/or Thr(tBu), reduction led incomplete removal group. After feasibility study, it can be concluded that combined use thioanisole DMS slightly higher quantity than H2O 1% DTT beneficial. optimal obtained if carried out two steps: initial treatment TFA/TIS/H2O/thioanisole/DMS/1% (70:5:5:10:10) for 30 min followed by up an 80% proportion continued 150 min.