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Synthesis of a β-strand mimetic based on a pyridine scaffold
Umeå University, Faculty of Science and Technology, Chemistry.
Umeå University, Faculty of Science and Technology, Chemistry.
2006 (English)In: Tetrahedron, ISSN 0040-4020, Vol. 62, no 47, 10937-10944 p.Article in journal (Refereed) Published
Abstract [en]

A synthetic route to a 2,4-disubstituted pyridine as a potential β-strand mimetic has been developed and applied in the synthesis of a tripeptidomimetic of Leu-Gly-Gly. The pyridine scaffold replaces the central glycine, and is substituted with analogues of leucine and glycine in positions 4 and 2, respectively. 2-Fluoro-4-iodopyridine was chosen as the functionalized scaffold and was substituted with protected leucinal in position 4 via a Grignard exchange reaction using iso-propyl magnesium chloride. The glycine moiety was introduced in position 2 via a nucleophilic aromatic substitution reaction (SNAr) facilitated by microwave irradiation. The synthetic sequence involved 12 steps with an overall yield of 7%.

Place, publisher, year, edition, pages
2006. Vol. 62, no 47, 10937-10944 p.
Keyword [en]
β-Strand mimetic, 2-Aminopyridine, Grignard exchange reaction, Nucleophilic aromatic substitution
URN: urn:nbn:se:umu:diva-2275DOI: 10.1016/j.tet.2006.08.080OAI: diva2:140204
Available from: 2007-05-03 Created: 2007-05-03Bibliographically 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.
Peptidomimetics, beta-turn, beta-strand, pyridine scaffold, Grignard exchange reaction, SNAr reaction, thrombin inhibitor, Leu-enkephalin.
National Category
Organic Chemistry
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)
Available from: 2007-05-03 Created: 2007-05-03 Last updated: 2009-08-27Bibliographically approved

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