Cyclization of disulfide‐containing peptides in solid‐phase synthesis

FERNANDO ALBERICIO, ROBERT P. HAMMER, CARLOS GARCÍA‐ECHEVERRÍA, M. ANTÒNIA MOLINS, JANE L. CHANG, MARK C. MUNSON, MIQUEL PONS, ERNEST GIRALT, GEORGE BARANY

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Abstract

Disulfide‐containing peptides may be obtained in good yields and purities when oxidations are carried out on peptide chains anchored to polymeric supports used for solid‐phase synthesis. Such approaches take advantage of the pseudo‐dilution phenomenon which favors intramolecular processes. A variety of procedures have been demonstrated using the related model peptides Ac‐Cys‐Pro‐d Val‐Cys‐NH2 and Ac‐Pen‐Pro‐d Val‐Cys‐NH2 (which both readily assume a type II β‐turn conformation that becomes stabilized by a 14‐membered disulfide‐containing intramolecular ring), and oxytocin (conformationally mobile 20‐membered disulfide ring). Both Boc and Fmoc were used for Nα‐amino protection, the β‐thiols of cysteine or penicillamine were blocked by S‐acetamidomethyl (Acm), S‐9‐fluorenylmethyl (Fm), or S‐trityl (Trt), and compatible anchoring linkages included HF‐labile 4‐methylbenzhydrylamide (MBHA), TFA‐labile tris (alkoxy)benzylamide (PAL), and photolabile o‐nitrobenzylamide (Nonb). Assemblies of linear sequences proceeded smoothly, and polymer‐supported oxidations were carried out in a variety of ways either directly or after deblocking to the resin‐bound dithiol. Chains were released from the support without substantial damage to the disulfide bridges, and overall yields were as high as 60‐90%.

Original languageEnglish (US)
Pages (from-to)402-413
Number of pages12
JournalInternational Journal of Peptide and Protein Research
Volume37
Issue number5
DOIs
StatePublished - May 1991

Keywords

  • acid‐labile tris(alkoxy)benzylamide handle
  • deprotection/oxidation of cysteine and penicillamine
  • disulfide bridges
  • oxytocin
  • photolabile ortho‐nitrobenzylamide handle
  • pseudo‐dilution
  • solid‐phase peptide synthesis
  • β‐turn model peptide

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