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Towards the Development of Photoswitchable β-Hairpin Mimetics
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry, Organic Chemistry.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Peptide secondary structure mimetics are important tools in medicinal chemistry, as they provide analogues of endogeneous peptides with new physicochemical and pharmacological properties. The β-hairpin motif has been shown to be involved in numerous physiological processes, among others in regulation of eucariotic gene transcription. This thesis addresses the design, synthesis and conformational analysis of photoswitchable β-hairpin mimetics.

The developmental work included the establishment of an improved procedure for cross coupling of aryl halides with terminal alkynes. Microwave mediated Sonogashira couplings in closed vessels were optimized under homogeneous and solid-phase conditions furnishing excellent yields for a large variety of substrates within 5 – 25 minutes. In addition, microwave heating was shown not to have any non-conventional effect on the reaction rate.

Furthermore, the most important factors affecting β-hairpin stability were evaluated. Studies of tetrapeptide and decapeptide analogues revealed the essential role of the β-turn in initiation of hairpin folding. Moreover, hydrogen bonding was shown to be the main interchain stabilizing force, whereas hydrophobic interactions were found to be relatively weak. Nevertheless, hydrophobic packing appears to provide an important contribution to the thermodynamic stability of β-hairpins.

Photoswitchable peptidomimetics were prepared by incorporation of various stilbene moieties into tetra- and decapeptides. Synthesis, photochemical isomerisation and spectroscopic conformational analysis of the compounds were performed.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2004. , p. 90
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 950
Keywords [en]
Organic chemistry, β-hairpin, peptidomimetics, Sonogashira, NMR, photochemistry, microwave, peptide, palladium
Keywords [sv]
Organisk kemi
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-4057ISBN: 91-554-5897-1 (print)OAI: oai:DiVA.org:uu-4057DiVA, id: diva2:164205
Public defence
2004-04-02, B41, BMC, Husargatan 3, 751 23 Uppsala, 10:15
Opponent
Supervisors
Available from: 2004-03-11 Created: 2004-03-11Bibliographically approved
List of papers
1. Rapid Homogeneous-Phase Sonogashira Coupling Reactions Using Controlled Microwave Heating
Open this publication in new window or tab >>Rapid Homogeneous-Phase Sonogashira Coupling Reactions Using Controlled Microwave Heating
2001 In: Journal of Organic Chemistry, Vol. 66, no 12, p. 4165-4169Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91463 (URN)
Available from: 2004-03-11 Created: 2004-03-11Bibliographically approved
2. Rapid Microwave Promoted Sonogashira Coupling Reactions on Solid Phase
Open this publication in new window or tab >>Rapid Microwave Promoted Sonogashira Coupling Reactions on Solid Phase
2003 (English)In: Journal of Organic Chemistry, Vol. 68, no 16, p. 6431-6434Article in journal (Refereed) Published
Abstract [en]

A microwave-enhanced, rapid, and efficient solidphase version of the Sonogashira reaction is presented. It has been applied to the coupling of aryl iodides and bromides with various acetylene derivatives giving excellent yields in 15 to 25 min. The scopes of homogeneous, solventless, and solid-phase conditions for Sonogashira coupling of aryl halides are compared.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-91464 (URN)10.1021/jo034284s (DOI)
Available from: 2004-03-11 Created: 2004-03-11 Last updated: 2011-01-05
3. Insight into β-Hairpin Stability: A Structural and Thermodynamic Study of Diastereomeric β-Hairpin Mimetics
Open this publication in new window or tab >>Insight into β-Hairpin Stability: A Structural and Thermodynamic Study of Diastereomeric β-Hairpin Mimetics
2002 In: New Journal of Chemistry, Vol. 26, p. 834-843Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91465 (URN)
Available from: 2004-03-11 Created: 2004-03-11Bibliographically approved
4. Synthesis and Conformational Analysis of Novel Stibene-type Peptidomimetics
Open this publication in new window or tab >>Synthesis and Conformational Analysis of Novel Stibene-type Peptidomimetics
Show others...
Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-91466 (URN)
Available from: 2004-03-11 Created: 2004-03-11Bibliographically approved
5. Synthesis and Conformational Analysis of Novel β-Hairpin mimetics. Factors Affecting Stability and Incorporation of a Photoswitchable Dipeptide Mimic
Open this publication in new window or tab >>Synthesis and Conformational Analysis of Novel β-Hairpin mimetics. Factors Affecting Stability and Incorporation of a Photoswitchable Dipeptide Mimic
Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-91467 (URN)
Available from: 2004-03-11 Created: 2004-03-11Bibliographically approved

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