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Synthesis and characterization of photoswitchable stiff-stilbene based amino acid derivatives
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Synthetic routes towards the Boc-protected amino acids 1 and 2 incorporating the stiff stilbene chromophore via the corresponding indanone carboxylic acids have been devised. Crucial steps are a reductive McMurry coupling of the indanone carboxylic acids, yielding stiff stilbene dicarboxylic acid esters. Hydrolysis to the monoester and conversion to the azides, followed by a Curtius rearrangement afforded the Boc-protected amino acid ester 1.

Keyword [en]
Peptidomimetics
National Category
Organic Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-267829OAI: oai:DiVA.org:uu-267829DiVA: diva2:874514
Funder
Swedish Research Council, 621-2012-3379
Available from: 2015-11-27 Created: 2015-11-27 Last updated: 2016-01-13
In thesis
1. Light-Triggered Conformational Switches for Modulation of Molecular Recognition: Applications for Peptidomimetics and Supramolecular Systems
Open this publication in new window or tab >>Light-Triggered Conformational Switches for Modulation of Molecular Recognition: Applications for Peptidomimetics and Supramolecular Systems
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The main focus of this thesis is on photochemical modulation of molecular recognition in various host-guest systems. This involves the design, synthesis and integration of light-triggered conformational switches into peptidomimetic guests and molecular tweezer hosts. The impact of the switches on guest and host structures has been assessed by spectroscopic and computational conformational analysis. Effects of photochemical structure modulation on molecular recognition in protein-ligand and supramolecular host-guest systems are discussed.

Phototriggerable peptidomimetic inhibitors of the enzyme M. tuberculosis ribonucleotide reductase (RNR) were obtained by incorporation of a stilbene based amino acid moiety into oligopeptides between 3-9 residues long (Paper I). Interstrand hydrogen bond probability in the E and Z forms of the peptidomimetics was used as a tool for predicting conformational preferences. Considerable differences in inhibitory potency for the E and Z photoisomers were demonstrated in a binding assay.

In order to advance the concept of photomodulable inhibitors, synthetic routes towards amino acid derivatives based on the more rigid stiff-stilbene chromophore were developed (Paper II).  The effect of E-Z isomerization on the conformational properties of peptidomimetic inhibitors incorporating the stiff-stilbene chromophore was also assessed computationally (Paper III). It was indicated that inhibitors with the more rigid amino acid derivative should display larger conformational divergence between photoisomers than corresponding stilbene derivatives.

Bisporphyrin tweezers with enediyne and stiff-stilbene spacers have been synthesized, and the conformational characteristics imposed by the spacers have been studied and compared to a glycoluril linked tweezer. The effects of spacers on tweezer binding of diamine guests and helicity induction by chiral guests have been investigated (Paper IV). Connections between spacer flexibility and host-guest binding strength have been established. The structural properties of the stiff-stilbene spaced tweezer made it particularly susceptible to helicity induction by both monotopic and bitopic chiral guests. Finally, the possibility of photochemical bite-size variation of tweezers with photoswitchable spacers has been assessed. Initial studies have shown that photoisomerization of the tweezers is possible without photochemical decomposition. Conformational analyses indicate that isomerization should impact binding characteristics of the tweezers to a significant extent (Paper V).

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1329
Keyword
Bisporphyrin tweezers, peptidomimetics, host-guest systems, conformational analysis, supramolecular chemistry, photochemistry
National Category
Chemical Sciences
Research subject
Organic Chemistry; Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-267845 (URN)978-91-554-9431-5 (ISBN)
Public defence
2016-01-28, B41, BMC, Husargatan 3, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2016-01-04 Created: 2015-11-27 Last updated: 2016-01-13Bibliographically approved

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Blom, MagnusHuang, HaoGogoll, Adolf

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