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Synthesis and conformational studies of a β-turn mimetic incorporated in Leu-enkephalin
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2004 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 69, no 10, 3500-3508 p.Article in journal (Refereed) Published
Abstract [en]

A β-turn mimetic in which the four amino acids of a β-turn have been replaced by a 10-membered ring has been designed, synthesized, and subjected to conformational studies. In the mimetic, the intramolecular COi − HNi+3 hydrogen bond that is often found in β-turns has been replaced by an ethylene bridge. In addition, the amide bond between residues i and i + 1 was exchanged for a methylene ether isoster. Such a β-turn mimetic, based on the first four residues of Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu), was prepared in 15 steps. The synthesis relied on a β-azido alcohol prepared in five steps from Cbz-Tyr(tBu)-OH as a key, i-position building block. tert-Butyl bromoacetate, glycine, and a Phe-Leu dipetide were then used as building blocks for positions i + 1, i + 2, and i + 3, respectively. Conformational studies based on 1H NMR data showed that the β-turn mimetic was flexible, but that it resembled a type-II β-turn at low temperature. This low energy conformer closely resembled the structure determined for crystalline Leu-enkephalin.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2004. Vol. 69, no 10, 3500-3508 p.
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:umu:diva-2273DOI: 10.1021/jo0356863OAI: oai:DiVA.org:umu-2273DiVA: diva2:140202
Available from: 2007-05-03 Created: 2007-05-03 Last updated: 2012-10-11Bibliographically approved
In thesis
1. Synthesis of β-turn and pyridine based peptidomimetics
Open this publication in new window or tab >>Synthesis of β-turn and pyridine based peptidomimetics
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Despite the unfavorable pharmacokinetic properties associated with peptides, they are still of great interest in drug development due to a multitude of interesting biological functions. The development of peptidomimetics strives to maintain or improve the biological activity of a peptide concurrently with removing the unwanted properties. This thesis describes two synthetic approaches to peptidomimetics with particular emphasis on secondary structure mimetics.

First the design, synthesis and evaluation of two beta-turn mimetics incorporated in the endorphin Leu-enkephalin is presented. The beta-turn mimetics were stabilized by replacement of the intramolecular hydrogen bond with an ethylene bridge, and the amide bond between Tyr and Gly was replaced with an ether linkage. Linear analogues of the two mimetics were also synthesized. The peptidomimetics and their linear analogues were evaluated in a competitive binding assay at two opiate receptors, my and delta. One of the cyclized beta-turn mimetics was found to be a delta receptor antagonist with an IC50 value of 160 nM.

Second a synthetic strategy to a beta-strand mimetic using 2-fluoro-4-iodopyridine as scaffold is described. The synthesis involved a Grignard exchange reaction on the pyridine scaffold using an amino acid derivative as electrophile followed by an SNAr reaction using an amine as nucleophile. The synthesis of a tripeptidomimetic of Leu-Gly-Gly and attempts to introduce chiral building blocks at the C-terminal, as well as studies towards elongated mimetics are presented.

Two additional studies deal with the synthesis of two classes of potential thrombin inhibitors based on the pyridine scaffold. The first class contain pyridine as central fragment (P2 residue) substituted with a para-amidinobenzylamine group as P1 residue and various benzoyl groups as P3 residues. Three potential thrombin inhibitors were synthesized and found to be microM inhibitors in an enzymatic assay. In the second class, the pyridine ring serves as P3 residue. This class also lacks a strongly basic group in the P1 position. A small library of eight compounds were synthesized and evaluated in the enzymatic assay. Unfortunately, these compounds lacked inhibitory activity.

Place, publisher, year, edition, pages
Umeå: Kemi, 2007. 90 p.
Keyword
Peptidomimetics, beta-turn, beta-strand, pyridine scaffold, Grignard exchange reaction, SNAr reaction, thrombin inhibitor, Leu-enkephalin.
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-1104 (URN)978-91-7264-305-5 (ISBN)
Public defence
2007-05-26, KB3A9, KBC, Umeå Universitet, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2007-05-03 Created: 2007-05-03 Last updated: 2009-08-27Bibliographically approved
2. NMR as a tool in drug research: Structure elucidation of peptidomimetics and pilicide-chaperone complexes
Open this publication in new window or tab >>NMR as a tool in drug research: Structure elucidation of peptidomimetics and pilicide-chaperone complexes
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In the last decades NMR spectroscopy has become an invaluable tool both in academic research and in the pharmaceutical industry. This thesis describes applications of NMR spectroscopy in biomedicinal research for structure elucidation of biologically active peptides and peptidomimetics as well as in studies of ligand-protein interactions.

The first part of this thesis describes the theory and methodology of structure calculations of peptides using experimental restraints derived from NMR spectroscopy. This methodology has been applied to novel mimetics of the peptide hormones desmopressin and Leu-enkephalin. The results of these studies highlight the complicating issue of conformational exchange often encountered in structural determination of peptides and how careful analysis of experimental data as well as optimization of experimental conditions can enable structure determinations in such instances. Although the mimetics of both desmopressin and Leu-enkephalin were found to adopt the wanted conformations, they exhibited no or very poor biological activity. These results demonstrate the difficulties in designing peptidomimetics without detailed structural information of the receptors. A stereoselective synthetic route towards XxxΨ[CH2O]Ala pseudodipeptides is also presented. Such pseudodipeptides can be used as isosteric amide bond replacements in peptides in order to increase their resistance towards proteolytic degradation.

The second part of this thesis describes the study of the interaction between compounds that inhibit pilius assembly, pilicides, and periplasmic chaperones from uropathogenic Escherichia coli. Periplasmic chaperones are key components in assembly of pili, i.e. hair-like protein complexes located on the surface of Escherichia coli that cause urinary tract infections. Detailed knowledge about this interaction is important in understanding how pilicides can inhibit pilus assembly by binding to chaperones. Relaxation-edited NMR experiments were used to confirm the affinity of the pilicides for the chaperones and chemical shift mapping was used to study the pilicide-chaperone interaction surface. These studies show that at least two interaction sites are present on the chaperone surface and consequently that two different mechanisms resulting in inhibition of pilus assembly may exist.

Place, publisher, year, edition, pages
Umeå: Kemi, 2004. 66 p.
Keyword
Organic chemistry, NMR, structure calculations, peptidomimetics, desmopressin, Leu-enkephalin, chemical shift mapping, pilicides, chaperones, urinary tract infections., Organisk kemi
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-320 (URN)91-7305-724-X (ISBN)
Public defence
2004-10-08, sal KB3B1, KBC-huset, Umeå universitet, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2004-09-20 Created: 2004-09-20 Last updated: 2010-03-08Bibliographically approved

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