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Published on: May 15, 2012
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Automated solid-phase synthesis of metabolically stabilized triazolo-peptidomimetics
Xabier Guarrochena1,2,3,4,5, Barbara Kaudela1,2,3, Thomas L Mindt1,3,4,5
1Department of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria.
Summary
Automated synthesis of triazolo-peptidomimetics is now possible using a two-step method. This approach stabilizes peptide bonds and offers a versatile platform for drug discovery.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Peptide Chemistry
Background:
- 1,4-disubstituted 1,2,3-triazoles serve as crucial trans-amide bond surrogates.
- Metabolically stabilized peptidomimetics are vital in drug development.
- Previous synthesis of triazolo-peptidomimetics relied on manual methods.
Purpose of the Study:
- To develop an automated synthesis protocol for backbone-modified triazolo-peptidomimetics.
- To optimize reaction conditions for stability and efficiency in automated peptide synthesizers.
- To demonstrate the versatility of the automated method for diverse peptidomimetic synthesis.
Main Methods:
- Exploration of reaction conditions for diazo-transfer and copper-catalyzed azide-alkyne cycloaddition (CuAAC) reactions.
- Utilized an aqueous solution of diazo-transfer reagent (ISA·HCl) to enhance stability.
- Employed [Cu(CH3CN)4]PF6 and TBTA for the CuAAC reaction in an automated solid-phase peptide synthesis (SPPS) setup.
Main Results:
- Optimized conditions enabled the stable use of ISA·HCl and Cu(I) catalyst in solution.
- Successfully synthesized five structurally diverse triazolo-peptidomimetics (5-8 amino acid residues) using two resins.
- Achieved moderate to good purities (70-85%) with synthesis times of 9-12.5 hours.
Conclusions:
- Developed a robust and efficient automated two-step procedure for synthesizing triazolo-peptidomimetics.
- The methodology is versatile and applicable to various peptidomimetic structures.
- This advancement facilitates the production of metabolically stabilized peptidomimetics for pharmaceutical research.
