Unnatural Amino Acids

By: Matthias Junkers, Aldrich ChemFiles 2008, 8.7, 3.

Unnatural amino acids, the non-proteinogenic amino acids that either occur naturally or are chemically synthesized, are becoming more and more important as tools for modern drug discovery research. Due to their unlimited structural diversity and functional versatility, they are widely used as chiral building blocks and molecular scaffolds in constructing combinatorial libraries.1 They represent a powerful tool in drug discovery when incorporated into therapeutic peptidomimetics and peptide analogs. Used as molecular probes they can help to better understand the function of biological systems.2

Peptidomimetics have found widespread recognition as surrogates for therapeutic peptides derived from proteinacious amino acids because they may show improved in vivo stability, enhanced potency, better oral absorption, improved tissue distribution, and increased selectivity of biological response. In this context, unnatural amino acids can be used to alter the tertiary structure of a peptide. Side chain modifications allow the design of drug candidates with a perfect match to their biological target.

Sigma-Aldrich® is dedicated to becoming a strong partner for your Drug Discovery research by offering a broad and unique range of unnatural amino acid building blocks. In this section you will find recent additions to our amino acid portfolio including derivatives of glycine, phenylglycine, alanine, phenylalanine, and innovative α,α-disubstituted amino acids, as well as a comprehensive listing of proline derivatives and β-amino acids.

Nagase α,α-disubstituted Amino Acids

Chiral quaternary ammonium catalysts can be particularly useful in the field of asymmetric synthesis. Keji Maruoka and co-workers from Kyoto University have reported potent C2-symmetric ammonium salts that catalyze alkylation reactions under remarkably low catalyst loadings.3 Nagase, in close cooperation with Prof. Maruoka has applied his methodology in industrially viable procedures to synthesize α−monosubstituted and novel α,α-disubstituted α−amino acids by alkylation of alanine- (Scheme 1) and glycine-derived (Scheme 2) Schiff bases with alkyl halides. Research quantities of novel Nagase α,α-disubstituted amino acids are now available through Sigma-Aldrich®. Enantiopure allylalanines for example will open pathways to completely new structures. Rutjes and co-workers have already shown that the comparable allylglycine is a remarkable precursor for the synthesis of a broad range of building blocks.4

Scheme 1

Scheme 2

back to top Back to Top

Proline Derivatives

Proline is a non-polar, natural amino acid that forms a tertiary amide when incorporated into peptides. Thus, it is the only proteinogenic amino acid that does not act as a hydrogen bond donor in a peptide chain. Proline is known as a classical breaker of both the α-helical and β-sheet secondary structures in proteins and peptides, and it plays a crucial role in protein folding. Synthetic proline derivatives, mimetics and analogs offer further options to tune the biological, pharmaceutical, or physicochemical properties of peptides and proteins. In recent years proline derivatives and analogs have also found increasing popularity as organocatalysts in asymmetric synthesis.5

back to top Back to Top

β-Amino Acids and Homologs

Although they are less abundant than their α-analogues, β-amino acids occur in nature both in free form and bound to peptides. Oligomers composed exclusively of β-amino acids (so-called β-peptides) might be the most thoroughly investigated peptidomimetics. Besides being remarkably stable to metabolism, exhibiting slow microbial degradation, and inherently stable to proteases and peptidases, they fold into well-ordered secondary structures consisting of helices, turns, and sheets. In this respect, the most intriguing effects have been observed when β2-amino acids are present in the β-peptide backbone.6 A whole new “world” has emerged from the design of fascinating new peptidic macromolecules from β- and γ-homologated proteinogenic amino acids and other components.7 Sigma-Aldrich® is proud to be a leading supplier of β-amino acids. This ChemFiles presents a comprehensive list of available products.

back to top Back to Top

Materials

     

References

  1. Ma, J.S. Chem. Today 2003, 65.
  2. Dougherty, D.A. Curr Opin Chem Biol. 2000, 6, 645.
  3. (a) Kitamura, M. et al. Angew. Chem. Int. Ed. 2005, 44, 1549.(b) Ooi, T.;Maruoka, K. Aldrichimica Acta 2007, 40, 77.
  4. (a) Rutjes, F.P.J.T. et al. J. Org. Biol. Chem.2005, 3, 3435.(b) Rutjes, F.P.J.T. et al. J. Chem. Soc., Perkin Trans. 1 2000, 4197.
  5. (a) Vignola, N.; List, B. J. Am. Chem. Soc. 2003, 125, 450.(b) Dalko, P.I.;Moisan, L.; Angew. Chem. Int. Ed. 2004, 43, 5138.
  6. Lelais, G.; Seebach, D. Biopolymers 2004, 76, 206.
  7. Seebach, D.; Beck,A.K.; Bierbaum, D.J. Chem. & Biodiv. 2004, 1, 1111.

back to top Back to Top

Related Links