- AutorIn
- Robert Wodtke Technische Universität Dresden, Department of Chemistry and Food Chemistry, Dresden, Germany
- Gloria Ruiz-GómezTechnische Universität Dresden, Structural Bioinformatics, BIOTEC, Dresden, Germany
- Manuela KucharTechnische Universität Dresden, Department of Chemistry and Food Chemistry, Dresden, Germany
- M. Teresa Pisabarro
- Pavlina Novotná
- Marie Urbanová
- Jörg Steinbach
- Jens Pietzsch
- Reik Löser
- Titel
- Cyclopeptides containing the DEKS motif as conformationally restricted collagen telopeptide analogues
- Untertitel
- synthesis and conformational analysis
- Zitierfähige Url:
- https://nbn-resolving.org/urn:nbn:de:bsz:14-qucosa2-362801
- Quellenangabe
- Organic & Biomolecular Chemistry Erscheinungsort: Cambrigde
Verlag: Royal Society of Chemistry
Erscheinungsjahr: 2015
Jahrgang: 13
Heft: 6
Seiten: 1878-1896
E-ISSN: 1477-0539 - Erstveröffentlichung
- 2015
- Abstract (EN)
- The collagen telopeptides play an important role for lysyl oxidase-mediated crosslinking, a process which is deregulated during tumour progression. The DEKS motif which is located within the N-terminal telopeptide of the α1 chain of type I collagen has been suggested to adopt a βI-turn conformation upon docking to its triple-helical receptor domain, which seems to be critical for lysyl oxidase-catalysed deamination and subsequent crosslinking by Schiff-base formation. Herein, the design and synthesis of cyclic peptides which constrain the DEKS sequence in a β-turn conformation will be described. Lysine-side chain attachment to 2-chlorotrityl chloride-modified polystyrene resin followed by microwave-assisted solid-phase peptide synthesis and on-resin cyclisation allowed for an efficient access to head-to-tail cyclised DEKS-derived cyclic penta- and hexapeptides. An Nε-(4-fluorobenzoyl)lysine residue was included in the cyclopeptides to allow their potential radiolabelling with fluorine-18 for PET imaging of lysyl oxidase. Conformational analysis by ¹H NMR and chiroptical (electronic and vibrational CD) spectroscopy together with MD simulations demonstrated that the concomitant incorporation of a D-proline and an additional lysine for potential radiolabel attachment accounts for a reliable induction of the desired βI-turn structure in the DEKS motif in both DMSO and water as solvents. The stabilised conformation of the cyclohexapeptide is further reflected by its resistance to trypsin-mediated degradation. In addition, the deaminated analogue containing allysine in place of lysine has been synthesised via the corresponding ε-hydroxynorleucine containing cyclohexapeptide. Both ε-hydroxynorleucine and allysine containing cyclic hexapeptides have been subjected to conformational analysis in the same manner as the lysine-based parent structure. Thus, both a conformationally restricted lysyl oxidase substrate and product have been synthetically accessed, which will enable their potential use for molecular imaging of these important enzymes.
- Andere Ausgabe
- Link zum Artikel, der zuerst in der Zeitschrift 'Organic & Biomolecular Chemistry' erschienen ist.
DOI: 10.1039/c4ob02348j - Freie Schlagwörter (DE)
- Kollagen-Telopeptide, Tumorprogression, βI-Wend-Konformation, effizienten Zugang, Fluor-18, molekulare Bildgebung
- Freie Schlagwörter (EN)
- collagen telopeptides, tumour progression, βI-turn conformation, efficient access, fluorine-18, molecular imaging
- Klassifikation (DDC)
- 540
- Verlag
- Royal Society of Chemistry, London
- Förder- / Projektangaben
- Deutsche Forschungsgemeinschaft project A7 ID: SFB-TRR67
- Version / Begutachtungsstatus
- publizierte Version / Verlagsversion
- URN Qucosa
- urn:nbn:de:bsz:14-qucosa2-362801
- Veröffentlichungsdatum Qucosa
- 07.01.2020
- Dokumenttyp
- Artikel
- Sprache des Dokumentes
- Englisch
- Lizenz / Rechtehinweis