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Synthesis of β-turn and pyridine based peptidomimetics
Umeå University, Faculty of Science and Technology, Chemistry.
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 [en]
Peptidomimetics, beta-turn, beta-strand, pyridine scaffold, Grignard exchange reaction, SNAr reaction, thrombin inhibitor, Leu-enkephalin.
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-1104ISBN: 978-91-7264-305-5 (print)OAI: oai:DiVA.org:umu-1104DiVA: diva2:140206
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
List of papers
1. Synthesis and conformational studies of a β-turn mimetic incorporated in Leu-enkephalin
Open this publication in new window or tab >>Synthesis and conformational studies of a β-turn mimetic incorporated in Leu-enkephalin
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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
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-2273 (URN)10.1021/jo0356863 (DOI)
Available from: 2007-05-03 Created: 2007-05-03 Last updated: 2017-12-14Bibliographically approved
2. Synthesis and biological evaluation of leucine enkephalin turn mimetics
Open this publication in new window or tab >>Synthesis and biological evaluation of leucine enkephalin turn mimetics
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2006 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 4, no 3, 416-423 p.Article in journal (Refereed) Published
Abstract [en]

A cyclic Leu-enkephalin mimetic containing a 7-membered ring, and two linear analogues, has been prepared on solid phase. In the cyclic mimetic the intramolecular (1–4) hydrogen bond found in crystalline Leu-enkephalin has been replaced by an ethylene bridge. In addition, the amide bond between Tyr1 and Gly2 has been replaced by a methylene ether isostere and Gly3 has been deleted. The two linear analogues both contain the methylene ether isostere instead of the Tyr1-Gly2 amide bond and the shorter of the two lacks Gly3. The three compounds, and a β-turn mimetic analogous to the 7-membered turn mimetic but with Gly3 included, were evaluated for specific binding to µ- and δ-opioid receptors in rat brain membranes. With the exception of the β-turn mimetic the three other Leu-enkephalin analogues all bound with varying affinity to the µ- and δ-opioid receptors. From the results it could be concluded that Leu-enkephalin binds in a turn conformation to the opiate receptors, but that this conformation is not a (1–4) β-turn.

Keyword
Animals, Biomimetic Materials/*chemical synthesis/chemistry/metabolism/*pharmacology, Brain/cytology, Cyclization, Enkephalin; Leucine/*analogs & derivatives/*chemistry, Ligands, Molecular Structure, Rats, Receptors, Opioid, delta/metabolism, Receptors, Opioid, mu/metabolism
Identifiers
urn:nbn:se:umu:diva-2274 (URN)10.1039/b515618a (DOI)
Available from: 2007-05-03 Created: 2007-05-03 Last updated: 2017-12-14Bibliographically approved
3. Synthesis of a β-strand mimetic based on a pyridine scaffold
Open this publication in new window or tab >>Synthesis of a β-strand mimetic based on a pyridine scaffold
2006 (English)In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, 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%.

Keyword
β-Strand mimetic, 2-Aminopyridine, Grignard exchange reaction, Nucleophilic aromatic substitution
Identifiers
urn:nbn:se:umu:diva-2275 (URN)10.1016/j.tet.2006.08.080 (DOI)
Available from: 2007-05-03 Created: 2007-05-03 Last updated: 2017-12-14Bibliographically approved
4. Design, synthesis and biological evaluation of thrombin inhibitors based on a pyridine scaffold.
Open this publication in new window or tab >>Design, synthesis and biological evaluation of thrombin inhibitors based on a pyridine scaffold.
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2007 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 5, no 16, 2599-605 p.Article in journal (Other academic) Published
Abstract [en]

A series of 2,4-disubstituted pyridine derivatives has been designed, synthesised and evaluated as thrombin inhibitors. A Grignard exchange reaction was used to introduce various benzoyl substituents in position 4 of the pyridine ring, where they serve as P3 residues in binding to thrombin. In position 2 of the pyridine ring, a para-amidinobenzylamine moiety was incorporated as P1 residue by an SNAr reaction using ammonia as nucleophile followed by a reductive amination. A crystal structure obtained for one of the compounds in the active site of thrombin revealed that the basic amidine group of the inhibitor was anchored to Asp 189 at the bottom of the S1 pocket. A comparison with melagatran, bound in the active site of thrombin, revealed a good shape match but lack of hydrogen bonding possibilities in the S2–S3 region for the thrombin inhibitors reported in this study.

Identifiers
urn:nbn:se:umu:diva-5964 (URN)doi:10.1039/b705344d (DOI)18019535 (PubMedID)
Available from: 2007-12-04 Created: 2007-12-04 Last updated: 2017-12-14Bibliographically approved

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