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Solid-phase synthesis of arginine-containing peptides and fluorogenic substrates using a side-chain anchoring
Abdallah Hamzé1, Jean Martinez, Jean-François Hernandez
1Laboratoire des Aminoacides Peptides et Protéines, CNRS UMR 5810, Universités Montpellier I et II, Faculté de Pharmacie, 15 avenue Charles Flahault, BP 14491, 34093 Montpellier cédex 5, France.
The Journal of Organic Chemistry
|November 20, 2004
Summary
Researchers developed a novel, simplified solid-phase synthesis for arginine derivatives. This method efficiently produces fluorogenic substrates and arginine analogues for combinatorial synthesis, avoiding complex linkers.
Area of Science:
- Organic Chemistry
- Biochemistry
- Medicinal Chemistry
Background:
- Attaching amino acids to solid supports via side chains is crucial for modifying alpha-carboxylic groups, such as for fluorogenic substrate preparation.
- Anchoring arginine to resins typically requires a complex, multi-step linker synthesis due to its guanidinium group.
Purpose of the Study:
- To develop a simpler, more efficient method for synthesizing arginine derivatives on a solid support.
- To avoid the multi-step synthesis and difficult attachment of linkers for arginine side-chain anchoring.
Main Methods:
- A novel strategy was developed involving building the guanidine group directly on a Rink amide resin.
- Key steps included addition of an ornithine isothiocyanate derivative, S-methylation of thiourea, and guanidinylation with ammonium acetate.
- Resin cleavage yielded the final arginine-containing compound, with the resin's amine group incorporated into the guanidine.
Main Results:
- The method successfully synthesized a series of fluorogenic substrates for trypsin-like serine proteases in high yield and purity.
- It also enabled the generation of differentially substituted arginine derivatives, including Nomega-methyl- and Nomega-ethylarginines, from a single precursor.
- Intermediates like thiocitrulline and S-methylisothiocitrulline were also accessible, with free alpha-amine and carboxylic groups.
Conclusions:
- This simplified solid-phase synthesis method efficiently prepares arginine derivatives and fluorogenic substrates.
- The strategy is a powerful tool for combinatorial solid-phase synthesis of nitric oxide synthase inhibitors.
- It offers a versatile approach for generating diverse arginine analogues and intermediates.