129474-02-8Relevant academic research and scientific papers
Enzymatic synthesis of activated esters and their subsequent use in enzyme-based peptide synthesis
Nuijens, Timo,Cusan, Claudia,Schepers, Annette C.H.M.,Kruijtzer, John A.W.,Rijkers, Dirk T.S.,Liskamp, Rob M.J.,Quaedflieg, Peter J.L.M.
, p. 79 - 84 (2012/02/03)
Chemoenzymatic peptide synthesis is potentially the most cost-efficient technology for the synthesis of short and medium-sized peptides. However, there are still some limitations when challenging peptides, e.g. containing sterically demanding acyl donors, non-proteinogenic amino acids or proline residues, are to be synthesized. To remedy these limitations, special ester moieties have been used that are specifically recognized by the enzyme, e.g. guanidinophenyl, carboxamidomethyl (Cam) or trifluoroethyl (Tfe) esters, which, unfortunately, are notoriously difficult to synthesize chemically. Herein, we demonstrate that Cam and Tfe esters are very useful for Alcalase-CLEA mediated peptide synthesis using sterically demanding and non-proteinogenic acyl donors as well as poor nucleophiles, and combinations thereof. Furthermore, these esters can be efficiently synthesized by using the lipase Cal-B or Alcalase-CLEA. Finally, it is shown that the ester synthesis by Cal-B and subsequent peptide synthesis by Alcalase-CLEA can be performed simultaneously using a two-enzyme-one-pot approach with glycolamide or 2,2,2-trifluoroethanol as additive.
Synthesis of fused 1,2,5-triazepine-1,5-diones and some N2- and N3-substituted derivatives: Potential conformational mimetics for cis-peptidyl prolinamides
Lenman, Morag M.,Lewis, Arwel,Gani, David
, p. 2297 - 2311 (2007/10/03)
The synthesis of a new fused 1,2,5-triazepine-1,5-dione heterocycle, which is expected to mimic structural features of cis-peptldyl prolinamides, is described. The required parent heterocycle, corresponding to cis-glycy-(2S)-prolinamide, has been prepared in good yield by the cyclisation of N-(2-bromoacetylprolyl)-hydrazine which is itself generated in situ from the bromoacetyl proline methyl ester. Analogues corresponding to cis-(2R)-alanyl- and cis-(2S)-alanyl-(2S)-prolinamide have been similarly prepared from the appropriate N-(2-bromopropionyl)proline methyl esters and hydrazine hydrate where the cyclisation step, involving the displacement of bromide, has been shown to occur with inversion of configuration at C-2 of the propionyl moiety. Acylation at the N-3 position of the triazepine is equivalent to N-terminal acylation of the residue preceding the proline residue in cis-aminoacyl prolinamides. This has been achieved without incident using standard peptide coupling procedures. Extension at the 'C-terminal' has been achieved by preparing elaborated hydrazine precursors which are reacted with suitably activated esters of N-α-halogenoacylprolines, prior to cyclisation, to give the required fused triazepine dione. Thus it is possible to prepare constrained cis-peptidyl prolyl peptide mimetics of defined stereochemistry based upon this new triazepine dione in which all of the non-proline residues can be varied.
