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Copper–Alkyne Complexation Responsible for the Nucleolar Localization of Quadruplex Nucleic Acid Drugs Labeled by Click Reactions
Author(s) -
Lefebvre Joël,
Guetta Corinne,
Poyer Florent,
MahuteauBetzer Florence,
TeuladeFichou MariePaule
Publication year - 2017
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201703783
Subject(s) - bioorthogonal chemistry , click chemistry , nucleic acid , chemistry , alkyne , guanine , g quadruplex , azide , in vitro , chemical biology , biophysics , small molecule , combinatorial chemistry , stereochemistry , biochemistry , dna , nucleotide , biology , gene , organic chemistry , catalysis
Abstract G‐Quadruplex(es) (G4) are noncanonical nucleic‐acid structures found in guanine‐rich sequences. They can be targeted with small molecules (G4 ligands) acting as reporters, for tracking both in vitro and in cells. We explored the cellular localization of PhenDC 3 , one of the most powerful G4 ligands, by synthesizing two clickable azide and alkyne derivatives (PhenDC 3 ‐alk, PhenDC 3 ‐az) and labeling them in situ with the corresponding Cy5 click partners. A careful comparison of the results obtained for the copper‐based CuAAC and copper‐free SPAAC methodologies in fixed cells implicated Cu I /alkyne intermediates in the nonspecific localization of ligands (and fluorophores) to the nucleoli. By contrast, SPAAC yielded similar nucleoplasmic labeling patterns in fixed and live cells. Our findings demonstrate the need for great care when using CuAAC to localize drugs in cells, and show that SPAAC gives results that are more consistent between fixed and live cells.