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Molecules 2017, 22(12), 2160; doi:10.3390/molecules22122160

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

Department of Chemistry, University of Cyprus, 1 Panepistimiou Avenue, Aglandjia 2109, Nicosia, Cyprus
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Received: 27 October 2017 / Revised: 22 November 2017 / Accepted: 2 December 2017 / Published: 6 December 2017
(This article belongs to the Special Issue G-Quadruplex Ligands and Cancer)
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Abstract

Oligomeric compounds, constituted of consecutive N,O-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 (KD = 0.6 × 10−7 M−1 and 0.8 × 10−7 M−1, 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. View Full-Text
Keywords: pyridyl-oxazoles; N,O-oligoaryl ligands; G-quadruplexes; conformational transition; C–H activation pyridyl-oxazoles; N,O-oligoaryl ligands; G-quadruplexes; conformational transition; C–H activation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Rizeq, N.; Georgiades, S.N. Investigation of ‘Head-to-Tail’-Connected Oligoaryl N,O-Ligands as Recognition Motifs for Cancer-Relevant G-Quadruplexes. Molecules 2017, 22, 2160.

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