Chemical Synthesis and Biological Evaluation of Unusual Sulfur-Containing Peptides and Efforts Toward Chemical Synthesis of Crocin

  • Author / Creator
    Huang, Zedu
  • In order to minimize side reactions when preparing peptides containing a C-terminal cysteine residue, a method of protection of the carboxyl of the C-terminal cysteine as a cyclic ortho ester was developed. N-Fmoc-S-StBu cysteine cyclic ortho esters 31 (L) and 32 (D) were synthesized with excellent enantiomeric purity. This moiety was incorporated onto a solid support via a disulfide linkage, and model tripeptides (Gly-Phe-Cys) and the analgesic peptide, crotalphine, were synthesized with excellent diastereomeric purity. In the second chapter of this thesis, a structure-activity relationship (SAR) study of the crotalphine was developed. Eleven analogs were prepared to elucidate the essential structural features for the analgesic activity and identify an active analog with increased metabolic stability. The biological evaluation of these analogs is ongoing in the laboratory of our collaborators. The Vederas group discovered a new family of Class II bacteriocins, such as thuricin-β, featuring sulfur to α-carbon bridges. In the third chapter, efforts toward asymmetric synthesis of a bis-amino acid containing a thioether bridge were attempted. This bis-amino acid could be used as a standard to confirm the stereochemistry at the α-carbon of the modified residues using chiral GC-MS. Bis-amino acid derivative (126) was synthesized as a single diastereomer using chiral tricycloiminolactone 129 and efforts toward the removal of the auxiliary are ongoing. In the second part of the third chapter, a SAR study of thuricin-β was performed. The cysteine residues of thuricin-β were replaced by glycine, serine or alanine. All of the synthetic analogs were inactive against Bacillus firmus. In the future, cyclic analog 163, will be synthesized and evaluated for antimicrobial activity. Crocin is a major component of saffron and shows activity against various diseases. The last project of this thesis was towards chemical synthesis and biological evaluation of crocin and its analogs. The polyene acid 198 was synthesized in 10 steps from geranyl acetate. Attempts to attach this acid to β-D-glucose were unsuccessful. In the future, polyene ester 214 will be coupled to β-D-glucose or β-gentibiose. When the glycosylated products are obtained, they will be subjected to cross metathesis conditions to form crocin and its analogs.

  • Subjects / Keywords
  • Graduation date
    Fall 2012
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
  • Supervisor / co-supervisor and their department(s)
  • Examining committee members and their departments
    • Ganzle, Michael (Agriculture, Food & Nutritional Science)
    • Vederas, John (Chemistry)
    • Cairo, Christopher (Chemistry)
    • Harynuk, James (Chemistry)
    • Clive, Derrick (Chemistry)
    • Williams, Robert (Chemistry, Colorado State University)