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Methodological studies in solid phase synthesis: Linkers and applications of multi-component condensations
Stockholm University, Faculty of Science, Department of Neurochemistry.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Solid phase synthesis has become an increasingly important tool in the synthesis of oligopolymers and small organic molecules. This thesis covers three important areas in the solid phase synthesis technique: linker strategies, reduction methods and novel routes to complex heterocycles.

The synthesis of the OMPPA [4-(3-hydroxy-4-metylpentyl)phenyl acetic acid] linker is described. This linker is compatible with the Boc/Bzl protective group strategy, and yields peptide acids upon cleavage from solid support. The OMPPA linker is stable towards “low-acid” treatment and is self-scavenging during final cleavage of the peptide product from solid support. These properties are beneficial for peptide purity and yields.

The synthesis of the HMPPA [3-(4-hydroxymethylphenylsulfanyl)propanoic acid] linker is described. This safety catch linker is compatible with both Fmoc/tBu- and Boc/Bzl protective group strategies in solid phase peptide synthesis. The HMPPA linker is stable towards super acids yet final cleavage from solid support is performed by a relatively mild reductive acidolysis method, yielding peptide acids. It is suggested that this linker may be useful when synthesizing cyclic peptides on solid support. A new facile method for reducing cystine moieties is described. Adding metallic zinc to cystine containing peptides and proteins dissolved in slightly acidic aqueous and/or non-aqueous solutions, results in rapid disulfide reduction. This method is compatible with functional groups commonly present in peptides and proteins. The solid phase synthesis of oxygen-bridged tetrahydropyridones via a multi-component condensation reaction is described. Expected products were obtained in reasonable yields using both aromatic- and aliphatic ketones. This class of compounds has the general physico-chemical properties that are typical for drugs with high pharmacological activity.

Place, publisher, year, edition, pages
Stockholm: Institutionen för neurokemi , 2006. , 87 p.
Keyword [en]
Solid phase peptide synthesis, solid phase organic chemistry, linkers, self-scavenging, safety catch linker, cyclic peptides, reductive acidolysis, disulfides, reduction, metallic zinc, multi-component condensations, combinatorial chemistry
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:su:diva-922ISBN: 978-91-7155-2 (print)OAI: oai:DiVA.org:su-922DiVA: diva2:200651
Public defence
2006-04-27, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 13:00
Opponent
Supervisors
Available from: 2006-04-07 Created: 2006-04-07Bibliographically approved
List of papers
1. 4-(3-Hydroxy-4-methylpentyl)phenylacetic acid as a new linker for the solid phase synthesis of peptides with Boc chemistry
Open this publication in new window or tab >>4-(3-Hydroxy-4-methylpentyl)phenylacetic acid as a new linker for the solid phase synthesis of peptides with Boc chemistry
1999 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 40, no 2, 377-380 p.Article in journal (Refereed) Published
Abstract [en]

The anchoring the first amino acid in Boc chemistry to a 4-(3-hydroxy-4-methylpentyl)phenylacetic acid linker is described and compared to the conventional Pam resin. The peptidyl-4-(4-methyl-3-pentoxy)phenylacetamide linkage is slightly more stable to TFA than the Pam linker but in contrast to the Pam linker stable to cleavage of benzylic protective groups with TFMSA/DMS/TFA mixtures. This allows a mild and convenient two step deprotection procedure using the “low TFMSA-high HF”. In HF this new linker reacts preferentially in an intramolecular reaction forming a tetrahydronaphthalene derivative.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-25837 (URN)10.1016/S0040-4039(98)02316-8 (DOI)
Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2017-12-13Bibliographically approved
2. 3-(4-hydroxymethylphenylsulfanyl)propanoic acid (HMPPA) as a new safety catch linker in solid phase peptide synthesis
Open this publication in new window or tab >>3-(4-hydroxymethylphenylsulfanyl)propanoic acid (HMPPA) as a new safety catch linker in solid phase peptide synthesis
2006 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 32, no 7, 5829-5832 p.Article in journal (Refereed) Published
Abstract [en]

A new safety catch linker, 3-(4-hydroxymethylphenylsulfanyl)propanoic acid (HMPPA), is described for use in solid phase peptide synthesis. The linker is readily synthesized from commercially available chemicals in a more cost efficient way compared to similar reported linkers. The HMPPA linker is easily attached to an amino derivatized solid support followed by on-resin oxidation of the thioether to sulfoxide, thereby making the linker very stable towards strong acid treatment. Final resin cleavage is performed by reductive acidolysis.

Place, publisher, year, edition, pages
Elsevier Ltd, 2006
National Category
Neurosciences
Identifiers
urn:nbn:se:su:diva-25838 (URN)10.1016/j.tetlet.2006.04.138 (DOI)
Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2017-12-13Bibliographically approved
3. Metallic zinc reduction of disulfide bonds between cysteine residues in peptides and proteins
Open this publication in new window or tab >>Metallic zinc reduction of disulfide bonds between cysteine residues in peptides and proteins
2005 (English)In: International Journal of Peptide Research and Therapeutics, ISSN 1573-3149, Vol. 11, no 4, 261-265 p.Article in journal (Refereed) Published
Abstract [en]

The use of powdered metallic zinc in acidic solution for the reduction of disulfide bonds in peptides and proteins has been investigated. The method has several advantages over the traditional mereapto based reducing methods currently used; the reducing agent is readily available and inexpensive; reduction can be performed in weakly acidic solutions of water and/or acetonitrile; work up simply consists of a centrifugation step followed by pipeting the supernatant from the metal pellet, thereby greatly diminishing the risk of reoxidation as a more elaborate work up procedure could result in. As no mercapto compounds are added, there is no risk that the reducing agent will interfere in subsequent modification of the thiol functionality. Disulfides in a model peptide are reduced within 5 min in any mixture of water/acetonitrile containing 1% TFA, all disulfides in insulin is reduced within I h in any mixture of water/acetonitrile containing 5% acetic acid. To stress the convenience of the metallic zinc reduction method, the resulting thiol compound was subjected to two commonly employed reactions in peptide chemistry: Cys(Npys) directed disulfide formation (70% yield) and native chemical ligation between the reduced model peptide and Boc-Ala-p-metylthiobenzyl ester (65% yield of the ligation product plus disulfide formation between Cys and p-thiocresol).

Keyword
disulfides, reduction, metallic zinc, native chemical ligation, directed disulfide formation
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-25839 (URN)10.1007/s10989-005-8113-1 (DOI)000234291700004 ()
Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2015-03-09Bibliographically approved
4. Solid-phase synthesis of oxygen-bridged tetrahydropyridones
Open this publication in new window or tab >>Solid-phase synthesis of oxygen-bridged tetrahydropyridones
2001 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 42, no 39, 6953-6956 p.Article in journal (Refereed) Published
Abstract [en]

A solid-phase approach for the synthesis of oxygen-bridged tetrahydropyridones has been developed. A diamine is attached to Trt-Cl resin and condensed with different aliphatic or aromatic ketones and coumarin-3-carboxylic acid for 20 h and cleaved with 5% TFA in DCM, resulting in tri or tetracyclic products in moderate to high yield.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-25840 (URN)
Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2017-12-13Bibliographically approved

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