Investigation of 'Head-to-Tail'-Connected Oligoaryl N,O-Ligands as Recognition Motifs for Cancer-Relevant G-Quadruplexes

Oligomeric compounds, constituted of consecutive , -heteroaromatic rings, introduce useful and tunable properties as alternative ligands for biomolecular recognition. In this study, we have explored a synthetic scheme relying on Van Leusen oxazole formation, in conjunction with C-H activation of the...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2017-12, Vol.22 (12), p.2160
Main Authors: Rizeq, Natalia, Georgiades, Savvas N
Format: Article
Language:English
Subjects:
Affinity
c-Myc protein
Cancer
Circular Dichroism
conformational transition
Cross coupling
C–H activation
Deoxyribonucleic acid
DNA
Energy transfer
Fluorescence
Fluorescence resonance energy transfer
G-Quadruplexes
Humans
Ligands
Molecular Structure
Myc protein
N,O-oligoaryl ligands
Nucleotide Motifs
Oxazole
Oxazoles - chemistry
Porphyrins - chemistry
pyridyl-oxazoles
Recognition
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Summary:Oligomeric compounds, constituted of consecutive , -heteroaromatic rings, introduce useful and tunable properties as alternative ligands for biomolecular recognition. In this study, we have explored a synthetic scheme relying on Van Leusen oxazole formation, in conjunction with C-H activation of the formed oxazoles and their subsequent C-C cross-coupling to 2-bromopyridines in order to assemble a library of variable-length, 'head-to-tail'-connected, pyridyl-oxazole ligands. Through investigation of the interaction of the three longer ligands (5-mer, 6-mer, 7-mer) with cancer-relevant G-quadruplex structures (human telomeric/22AG and c-Myc oncogene promoter/Myc2345-Pu22), the asymmetric pyridyl-oxazole motif has been demonstrated to be a prominent recognition element for G-quadruplexes. Fluorescence titrations reveal excellent binding affinities of the 7-mer and 6-mer for a Na⁺-induced antiparallel 22AG G-quadruplex (K = 0.6 × 10 M and 0.8 × 10 M , respectively), and satisfactory (albeit lower) affinities for the 22AG/K⁺ and Myc2345-Pu22/K⁺ G-quadruplexes. All ligands tested exhibit substantial selectivity for G-quadruplex versus duplex (ds26) DNA, as evidenced by competitive Förster resonance energy transfer (FRET) melting assays. Additionally, the 7-mer and 6-mer are capable of promoting a sharp morphology transition of 22AG/K⁺ G-quadruplex.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules22122160