Conformationally Constrained Amino Acid Derivatives

Conformationally Constrained Amino Acid Derivatives

Published on 30/11/2021

Herein we present a series of alpha,alpha-cycle-disubstituted amino acid derivatives used in peptide design for their structure promoting effects as well as conformational rigidity.

Iris Biotech offers a series of Fmoc- and Boc-protected alpha,alpha-disubstituted amino acid derivatives bearing (hetero)cyclic substitutions. These portfolio additions include for example rigidized phenylglycines, phenylalanines, tryptophanes, amino-cycloalkane-carboxylic acids bearing six-, seven- and eight-membered rings, as well as substituted piperidine moieties.

Such derivatives can be used as constrained building blocks for structure activity relationship studies. Furthermore, alpha,alpha-disubstituted amino acids are widely used in peptide design because of their structure-promoting effects and increased conformational rigidity. Calpha,alpha-dialkylated amino acid residues containing either linear or cyclic alkyl side-chain substitutions have been shown to strongly stabilize helical conformations.

The interaction of a peptides with its corresponding receptor binding pocket and surrounding cavity is fundamental for its biological activity. Thus, the successful promotion of signaling cascades is highly dependent on the three-dimensional conformation of peptides. The synthesis of conformationally stable peptides via incorporation of (constrained) amino acid mimics is of high interest to improve stability, biological activity, subtype selectivity and overall performance.

Early reports in literature (J. Med. Chem. 1991; 34(10): 3125-3132) already describe the impact of the restriction of a phenylalanine residue in a cyclic opioid peptide analogue. Whereas the cyclic parent peptide displayed high affinity for the µ but also the d receptor subtype, a conformationally restricted analogue showed 4 times lower µ-receptor affinity but 65 times lower affinity for d receptors and, consequently, greatly improved selectivity.

With our commercially available derivatives, scientists can easily synthesize a diversified library of constrained peptides for structure activity relationship studies.

➔ Interested in other non-proteinogenic amino acid derivatives? Inquire for a custom synthesis of your derivative of choice!

References:

Conformational restriction of the phenylalanine residue in a cyclic opioid peptide analog: effects on receptor selectivity and stereospecificity; P. W. Schiller, G. Weltrowska, N. Tai Mai Dung, C. Lemieux, N. N. Chung, B. J. Marsden, B. C. Wilkes; J. Med. Chem. 1991; 34(10): 3125-3132. https://doi.org/10.1021/jm00114a023.

Preptin Analogues: Chemical Synthesis, Secondary Structure and Biological Studies; C. M. Buchanan, Z. Peng, A. Cefre, V. Sarojini; Chem. Biol. Drug Des. 2013; 82(4): 429-437. https://doi.org/10.1111/cbdd.12168.

Peptide helices with pendant cycloalkane rings. Characterization of conformations of 1-aminocyclooctane-1-carboxylic acid (Ac8c) residues in peptides; J. Pept. Sci. 2004; 10(3): 160-172. https://doi.org/10.1002/psc.507.

Agonist Activity at the Kinin B1 Receptor: Structural Requirements of the Central Tetrapeptide; P. Rovero, M. Pellegrini, A. Di Fenza, S. Meini, L. Quartara, C. A. Maggi, F. Formaggio, C. Toniolo, D. F. Mierke; J. Med. Chem. 2001; 44(2): 274-278. https://doi.org/10.1021/jm000319u.

A New Class of Pseudopeptide Antagonists of the Kinin B1 Receptor Containing Alkyl Spacers; C. Galoppini, S. Meini, M. Tancredi, A. Di Fenza, A. Triolo, L. Quartara, C. A. Magi, F. Formaggio, C. Toniolo, S. Mazzucco, A. Papini, P. Rovero; J. Med. Chem. 1999; 42(3): 409-414. https://doi.org/10.1021/jm980495r.

Entry to New Conformationally Constrained Amino Acids. First Synthesis of 3-Unsubstituted 4-Alkyl-4-carboxy-2-azetidinone Derivatives via an Intramolecular Nalpha-Calpha-Cyclization Strategy; G. Gerona-Navarro, M. Angeles Bonache, R. Herranz, M. T. García-López, R. González-Muñiz; J. Org. Chem. 2001; 66: 3538-3547.

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