Photo-Cross-Linking Probes for Trapping G-Quadruplex DNA

We have developed a straightforward synthetic pathway to a set of six photoactivatable G‐quadruplex ligands with a validated G4‐binding motif (the bisquinolinium pyridodicarboxamide PDC‐360A) tethered through various spacers to two different photo‐cross‐linking groups: benzophenone and an aryl azide...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2014-01, Vol.53 (4), p.994-998
Main Authors: Verga, Daniela, Hamon, Florian, Poyer, Florent, Bombard, Sophie, Teulade-Fichou, Marie-Paule
Format: Article
Language:English
Subjects:
Alkylation
Azides - chemistry
Benzophenones - chemistry
Biology
Cross-Linking Reagents - chemistry
Crosslinking
Deoxyribonucleic acid
Derivatives
DNA
G-Quadruplexes
Humans
Ligands
Molecular Structure
photo-cross-linking
photoactivatable probes
Photochemical Processes
Selectivity
Topology
Trapping
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Summary:We have developed a straightforward synthetic pathway to a set of six photoactivatable G‐quadruplex ligands with a validated G4‐binding motif (the bisquinolinium pyridodicarboxamide PDC‐360A) tethered through various spacers to two different photo‐cross‐linking groups: benzophenone and an aryl azide. The high quadruplex‐versus‐duplex selectivity of the PDC core was retained in the new derivatives and resulted in selective alkylation of two well‐known G‐quadruplexes (human telomeric G4 and oncogene promoter c‐myc G4) under conditions of harsh competition. The presence of two structurally different photoactivatable functions allowed the selective alkylation of G‐quadruplex structures at specific nucleobases and irreversible G4 binding. The topology and sequence of the quadruplex matrix appear to influence strongly the alkylation profile, which differs for the telomeric and c‐myc quadruplexes. The new compounds are photoactive in cells and thus provide new tools for studying G4 biology. Catch me if you can: A readily accessible set of photoactivatable G‐quadruplex (G4) ligands with a bisquinolinium core showed high G4‐versus‐duplex selectivity. Alkylation under UV/Vis irradiation occurred at G4 nucleobases located in either the loops or the external G‐quartets (see picture), depending on the cross‐linker and the topology of the quadruplex. These probes might be used to irreversibly trap G4 structures for the study of G4 biology.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201307413