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Keywords:

  • Cross-Linked Ethoxylate Acrylate Resin supports;
  • disulfide-bridged peptides;
  • Ellman's reagent;
  • oxidation;
  • penicillamine-containing sequences;
  • polymer-bound oxidant;
  • potassium ferricyanide;
  • solid-phase Ellman's reagent;
  • urotensin II antagonist

Abstract:  Formation of disulfide bonds in synthetic peptides is one of the more challenging transformations to achieve in peptide chemistry, in view of the possible formation of oligomeric by-products and other side reactions, as well as occasional solubility problems in aqueous oxidizing media. It was shown previously that 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB ≡ Ellman's reagent), when attached to polyethylene glycol-polystyrene (PEG-PSTM), controlled-pore glass (CPG), or modified Sephadex supports, was an effective oxidizing agent that promoted disulfide formation under mild conditions. More recently, this work was extended to Cross-Linked Ethoxylate Acrylate Resin (CLEAR) supports, because of their compatibility with both organic and aqueous solvent mixtures. The resultant new tool, termed CLEAR-OXTM, was used to conveniently produce several model cyclic disulfides with improved purities and yields, when compared with solution oxidations. A particularly striking example was the gram-scale oxidation of a urotensin II antagonist peptide containing a hindered penicillamine unit.