N-Alkyl Substituted Carboxy Linkers for Peptide Synthesis

N-Alkyl Substituted Carboxy Linkers for Peptide Synthesis

Published on 10.08.2021

Herein, we present Fmoc-protected N-alkyl-substituted carboxy linkers, which can be elongated by Fmoc-SPPS and can easily be linked to amino-functionalized solid supports. Read on to find out more about their advantages.

Typically, alkoxybenzaldehyde linkers are used as synthetic tools for the generation of N-substituted peptide amides. Treatment of such linkers with primary amines results in the formation of imines, which can finally be reduced to the desired secondary amines.

Herein, we present a more convenient route for the generation of N-substituted peptide amides. The presented Fmoc-protected N-alkyl-substituted carboxy-terminated linkers can easily be elongated using standard Fmoc-based solid phase chemistry and linked to amino-functionalized solid supports by standard coupling procedures, e.g. by using diisopropylcarbodiimide (DIC) and 1-hydroxy-7-azabenzotriazole (HOAt). After desired elongation or chemistry performed, the benzylic bond can be cleaved by addition of 90% TFA and appropriate scavengers, releasing the peptide from its solid support.

 

Coupling of the N-alkylated carboxy linker to a solid support and subsequent peptide elongation by SPPS.

One prominent example for such an N-alkylation is the peptide hormone Leuprorelin (structure shown below), also known as leuprolide, a synthetic agonist of natural gonadotropin-releasing hormone, used to treat e.g. prostate cancer and breast cancer. For this case, Iris Biotech’s Fmoc-N-ethyl-MPBA (RL‑3770) can be used to introduce the desired N-ethyl group.

 

Chemical structure of the peptide hormone Leuprorelin. N-ethyl substitution highlighted in blue.

Besides its ease of use, the procedure is readily scalable and can also be utilized for the generation of larger peptides/proteins by fragment assembly or cyclized peptides via triazole formation.

An alkyne-modified linker construct, e.g. RL-3780 with its propargyl-moiety, can be used for Cu(I)-mediated Click reaction with an azide functional group, either within the same peptide (intramolecular) for the generation of cyclized peptides, or of a second peptide (intermolecular) for fragment ligation allowing the generation of larger peptides/proteins, both via triazole formation.

The cleavage of the linker from the peptide can occur either as last step or prior to the cyclization reaction. As cyclization condition, for example treatment with CuBr and an excess of DBU in refluxing toluene is reported.

 

Schematic illustration of Click-induced ring-closure via triazole formation.

The triazole moiety is well recognized as an amide bioisostere: it closely mimics the geometric, steric, and electronic features of a trans-amide bond and can likewise participate in hydrogen bonding and dipole-dipole interactions. These findings are in line with the experimental observation of several publications, in which the analyzed molecules retained their biological activity upon replacement of the amide bond by a triazole moiety.

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➔ You are looking for a different derivative? Get in contact for the custom synthesis of your N-substituted linker derivative of choice!

➔ Working on cyclized peptides? See our Cyclic Peptides Brochure 

 

References:

  • Synthesis of a biologically active triazole-containing analogue of cystatin A through successive peptidomimetic alkyne-azide ligations; I. E. Valverde, F. Lecaille, G. Lalmanach, V. Aucagne, A. F. Delmas; Angew. Chem. Int. Ed. Engl. 2012; 51(3): 718-722. https://doi.org/10.1002/anie.201107222.

  • Biomimetic Screening of Class-B G Protein-Coupled Receptors; C. Devigny, F. Perez-Balderas, B. Hoogeland, S. Cuboni, R. Wachtel, C. P. Mauch, K. J. Webb, J. M. Deussing, F. Hausch; J. Am. Chem. Soc. 2011; 133(23): 8927-8933. https://doi.org/10.1021/ja200160s.

  • Backbone Amide Linker Strategy for the Synthesis of 1,4-Triazole-Containing Cyclic Tetra- and Pentapeptides; J. Springer, K. R. de Cuba, S. Calvet-Vitale, J. A. J. Geenevasen, P. H. H. Hermkens, H. Hiemstra, J. H. van Maarseveen; Eur. J. Chem. 2008; 15: 2592-2600. https://doi.org/10.1002/ejoc.200800143.

  • An alternative method for the preparation of resin-bound secondary amines; R. E. Austin, C. A. Waldraff, F. Al-Obeidi; Tetrahedron Lett. 2002; 43(19): 3555-3556. https://doi.org/10.1016/S0040-4039(02)00569-5.  

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