Cyclopeptides containing the DEKS motif as conformationally restricted collagen telopeptide analogues : synthesis and conformational analysis

Medientyp: E-Artikel

Titel: Cyclopeptides containing the DEKS motif as conformationally restricted collagen telopeptide analogues : synthesis and conformational analysis

Beteiligte: Wodtke, Robert [VerfasserIn]; Ruiz-Gómez, Gloria [VerfasserIn]; Kuchar, Manuela [VerfasserIn]; Pisabarro, M. Teresa [VerfasserIn]; Novotná, Pavlina [VerfasserIn]; Urbanová, Marie [VerfasserIn]; Steinbach, Jörg [VerfasserIn]; Pietzsch, Jens [VerfasserIn]; Löser, Reik [VerfasserIn]

Erschienen: London : Royal Society of Chemistry, [2020]

Sprache: Englisch

DOI: 10.1039/c4ob02348j

Schlagwörter: βI-Wend-Konformation ; collagen telopeptides ; tumour progression ; effizienten Zugang ; science-chemistry ; Fluor-18 ; molekulare Bildgebung ; βI-turn conformation ; molecular imaging ; efficient access ; Kollagen-Telopeptide ; Chemie und Pharmazie ; fluorine-18 ; Tumorprogression

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Anmerkungen: Hinweis: Link zum Artikel, der zuerst in der Zeitschrift 'Organic & Biomolecular Chemistry' erschienen ist. DOI: 10.1039/c4ob02348j

Beschreibung: 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.

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