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A Direct, Early Stage Guanidinylation Protocol for the Synthesis of Complex Aminoguanidine-containing Natural Products
Published on: September 9, 2016
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Guanidine Additive Enabled Intermolecular ortho-Phthalaldehyde-Amine-Thiol Three-Component Reactions for Modular
Carina Hey Pui Cheung1, Tin Hang Chong1, Tongyao Wei1
1Department of Chemistry, State Key Laboratory of Synthetic Chemistry, The University of Hong Kong, Hong Kong SAR, P. R. China.
Angewandte Chemie (International Ed. in English)
|January 9, 2023
Summary
Guanidine enables efficient synthesis of peptide conjugates using ortho-phthalaldehyde (OPA) chemistry. This discovery facilitates modular construction of peptide-peptide and peptide-drug structures with high yields.
Area of Science:
- Organic Chemistry
- Bioconjugation Chemistry
- Medicinal Chemistry
Background:
- Ortho-phthalaldehyde (OPA) is increasingly used for protein and peptide modification via OPA-amine reactions.
- Historically, intermolecular OPA-amine-thiol reactions required excess thiol reagents for 1-thio-isoindole derivative formation.
Purpose of the Study:
- To develop a stoichiometric method for the intermolecular OPA-amine-thiol reaction.
- To enable modular construction of complex peptide and peptide-drug conjugates.
Main Methods:
- Investigated guanidine as an additive to control the OPA-amine-thiol three-component reaction.
- Synthesized peptide-peptide and peptide-drug conjugates using unprotected peptides and modified OPA derivatives.
Main Results:
- Guanidine effectively switched the reaction to a stoichiometric process.
- Synthesized 12 model peptide-peptide conjugates and 6 peptide-drug conjugates with high conversions and yields.
- Demonstrated the versatility of the reaction through further functionalization of a conjugate product.
Conclusions:
- Guanidine is a key additive for efficient and stoichiometric OPA-based bioconjugation.
- This method provides a versatile and flexible approach for constructing peptide-peptide and peptide-drug conjugates.
- The developed reaction expands the toolkit for modular synthesis in bioconjugation and medicinal chemistry.
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