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β2-Amino Acids in the Design of Conformationally Homogeneous cyclo-Peptide Scaffolds
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
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2006 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 71, no 18, p. 6814-6821Article in journal (Refereed) Published
Abstract [en]

Herein, we report studies on the influence of chiral, beta(2)-amino acids in the design of conformationally homogeneous cyclic tetrapeptide scaffolds. The cyclic alpha-tetrapeptide cyclo(-Phe-D-Pro-Lys-Phe-) (1) and its four mixed analogues, having one of the alpha-Phe replaced by either an (S)-or an (R)-beta(2)hPhe residue (i.e., cyclo(-(R)-beta(2)hPhe-D-Pro-Lys-Phe) (2a), cyclo(-(S)-beta(2)hPhe-D-Pro-Lys-Phe-) (2b), cyclo(-Phe-D-Pro-Lys-(R)-beta(2)hPhe-) (3a), and cyclo(- Phe- D- Pro- Lys-( R)-, 2hPhe-) ( 3b)), were all synthesized through solidphase procedures followed by solution- phase cyclization. Initially, all five cyclo- peptides were analyzed by H-1 NMR spectroscopic studies in different solvents and at variable temperatures. Subsequently, a detailed 2D NMR spectroscopic analysis of three of the mixed peptides in water was performed, and the information thus extracted was used as restraints in a computational study on the peptides' conformational preference. An X- ray crystallographic study on the side chain- protected (Boc) 2a revealed the solid- state structure of this peptide. The results presented herein, together with previous literature data on beta(3)-amino acid residues, conclusively demonstrate the potential of beta-amino acids in the design of conformationally homogeneous cyclic peptides that are homologous to peptides with known applications in biomedicinal chemistry and as molecular receptors.

Place, publisher, year, edition, pages
2006. Vol. 71, no 18, p. 6814-6821
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95283DOI: 10.1021/jo060854nISI: 000240020100013PubMedID: 16930031OAI: oai:DiVA.org:uu-95283DiVA, id: diva2:169442
Available from: 2006-12-22 Created: 2006-12-22 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Conformational Stability!?: Synthesis and Conformational Studies of Unnatural Backbone Modified Peptides
Open this publication in new window or tab >>Conformational Stability!?: Synthesis and Conformational Studies of Unnatural Backbone Modified Peptides
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The beauty of the wide functionality of proteins and peptides in Nature is determined by their ability to adopt three-dimensional structures. This thesis describes artificial molecules developed to mimic secondary structures similar to those found crucial for biological activities.

In the first part of this thesis, we focused on post-translational modifications of a class of unnatural oligomers known as β-peptides. Through the design and synthesis of a glycosylated β3-peptide, the first such hybrid conjugate was reported. In this first report, a rather unstable 314-helical structure was found. Subsequently, a collection of six new glycosylated β3-peptides was synthesized with the aim to optimize the helical stability in water.

The ability of natural proteins, i.e. lectins, to recognize the carbohydrate residue on these unnatural peptide backbones was investigated through a biomolecular recognition study.

The second part of this thesis concerns the design of conformationally homogeneous scaffolds, which could be of importance for biomedical applications. In paper V, four- and five-membered cyclic all-β3-peptides were investigated for this purpose. In a subsequent paper, a completely different strategy was employed; herein, the ability of a single β2-amino acid to restrict the conformational freedom of a cyclic α-peptide was studied.

In the third part of this thesis, we synthesized and investigated the folding propensities of novel backbone modified oligomers, i.e. β-peptoids (N-substituted β-Ala) with α-chiral side chains.

The collective results of these studies have established the procedures required for synthesis of glycosylated β-peptides and deepened our understanding of the factors governing folding among such oligomers. Moreover, it was established that β-amino acids can be a useful tool to increase conformational stability of cyclic peptides.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. p. 78
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 253
Keywords
Organic chemistry, Conformational investigations, β-peptides, glycosylation, biomolecular recognition, cyclic β³-peptides, cyclic mixed α/β²-peptides, β-peptoids, Organisk kemi
Identifiers
urn:nbn:se:uu:diva-7420 (URN)91-554-6759-8 (ISBN)
Public defence
2007-01-13, B42, BMC, Husargatan 3, Uppsala, 10:15
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Supervisors
Available from: 2006-12-22 Created: 2006-12-22Bibliographically approved

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Norgren, Anna S.

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