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Light-Triggered Conformational Switches for Modulation of Molecular Recognition: Applications for Peptidomimetics and Supramolecular Systems
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Synthetical Organic Chemistry.
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 [en]
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: urn:nbn:se:uu:diva-267845ISBN: 978-91-554-9431-5 (print)OAI: oai:DiVA.org:uu-267845DiVA: diva2:874570
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
List of papers
1. Phototriggerable peptidomimetics for the inhibition of Mycobacterium turberculosis ribonucleotide reductase by targeting protein-protein binding
Open this publication in new window or tab >>Phototriggerable peptidomimetics for the inhibition of Mycobacterium turberculosis ribonucleotide reductase by targeting protein-protein binding
Show others...
2015 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 13, no 9, 2612-2621 p.Article in journal (Refereed) Published
Abstract [en]

Incorporation of an artificial amino acid 2 with a stilbene chromophore into peptidomimetics with three to nine amino acids yields phototriggerable candidates for inhibition of the binding between the R1 and R2 subunits of the M. tuberculosis ribonucleotide reductase (RNR). Interstrand hydrogen bond probability was used as a guideline for predicting conformational preferences of the photoisomers. Binding of these inhibitors has been rationalized by docking studies with the R1 unit. Significant differences in binding of the photoisomers were observed. For the shorter peptidomimetics, stronger binding of the Z isomer might indicate hydrophobic interactions between the stilbene chromophore and the binding site.

National Category
Organic Chemistry Medicinal Chemistry
Research subject
Chemistry with specialization in Organic Chemistry; Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-239491 (URN)10.1039/C4OB01926A (DOI)000350144600018 ()25580895 (PubMedID)
Funder
Swedish Research Council
Available from: 2014-12-28 Created: 2014-12-28 Last updated: 2017-12-05Bibliographically approved
2. Synthesis and characterization of photoswitchable stiff-stilbene based amino acid derivatives
Open this publication in new window or tab >>Synthesis and characterization of photoswitchable stiff-stilbene based amino acid derivatives
(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
Peptidomimetics
National Category
Organic Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-267829 (URN)
Funder
Swedish Research Council, 621-2012-3379
Available from: 2015-11-27 Created: 2015-11-27 Last updated: 2016-01-13
3. Photoswitchable peptidomimetics with a stiff-stilbene chromophore for inhibition of Mycobacterium tuberculosis RNR
Open this publication in new window or tab >>Photoswitchable peptidomimetics with a stiff-stilbene chromophore for inhibition of Mycobacterium tuberculosis RNR
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Peptidomimetics incorporating two amino acids 1 and 2 with a stiff stilbene chromophore have been screened by a computational study and compared to a previously investigated analog 3 with stilbene chromophore. The effect of E-Z isomerization of the chromophores on the conformational properties of the petidomimetics was assessed via the frequency of hydrogen bonding between the two peptide strands attached to either side of the chromophore. Substantial differences between the three amino acids were thus indicated, in line with the anticipated effect of chromophore rigidity variation.

Keyword
Peptidomimetics, conformational analysis
National Category
Organic Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-267830 (URN)
Funder
Swedish Research Council, 621-2012-3379
Available from: 2015-11-27 Created: 2015-11-27 Last updated: 2016-01-13
4. Synthesis and Properties of Bis-Porphyrin Molecular Tweezers: Effects of Spacer Flexibility on Binding and Supramolecular Chirogenesis
Open this publication in new window or tab >>Synthesis and Properties of Bis-Porphyrin Molecular Tweezers: Effects of Spacer Flexibility on Binding and Supramolecular Chirogenesis
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2016 (English)In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 21, no 1Article in journal (Refereed) Published
Abstract [en]

Abstract: Ditopic binding of various dinitrogen compounds to three bisporphyrin molecular tweezers with spacers of varying conformational rigidity, incorporating the planar ene-diyne (1), the helical stiff stilbene (2), or the semirigid glycoluril motif fused to  the porphyrins (3) are compared. Binding constants Ka = 10^4 to 10^6 M^-1 reveal subtle  differences between these tweezers, that are discussed in terms of porphyrin dislocation  modes. Exciton coupled circular dichroism (ECCD) of complexes with chiral dinitrogen  guests provides experimental evidence for the conformational properties of the tweezers. The results are further supported and rationalized by conformational analysis.

Keyword
Bisporphyrin tweezers, metalloporphyrins, porphyrinoids, host-guest chemistry, supramolecular chemistry, chirogenesis, chirality transfer, exciton coupled circular dichroism, conformational analysis
National Category
Organic Chemistry Engineering and Technology
Research subject
Chemistry with specialization in Organic Chemistry; Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-267826 (URN)10.3390/molecules21010016 (DOI)000369485600001 ()
Funder
Swedish Research Council, 621-2012-3379Swedish Research Council, 621-2011-4423
Available from: 2015-11-27 Created: 2015-11-27 Last updated: 2017-12-01Bibliographically approved
5. Photomodulable bis-porphyrin molecular tweezers as dynamic host systems for diamine guests
Open this publication in new window or tab >>Photomodulable bis-porphyrin molecular tweezers as dynamic host systems for diamine guests
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Bisporphyrin molecular tweezers with an enediyne (1) or a stiff stilbene (2) photoswitchable spacer are proposed as systems for modulation of bitopic binding to diamine guests via E/Z photoisomerization. The photoisomerization has been monitored by UV-Vis and 1H NMR spectroscopy and occurs without side reactions such as Bergman cyclization. Possible applications are rationalized in terms of competitive binding involving monoamine/diamine mixtures, and are supported by conformational analysis of the envisioned host-guest complexes. Binding dynamics for conformationally flexible guests show significantly different performance of aliphatic 1,w-diamine guests with varying N-N distance.

Keyword
Bisporphyrin tweezers, supramolecular chemistry, photochemistry
National Category
Organic Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-267833 (URN)
Funder
Swedish Research Council, 621-2012-3379
Available from: 2015-11-27 Created: 2015-11-27 Last updated: 2016-01-13

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