Bioactive papaverine derivatives bind G-quadruplexes selectively |
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Authors: | Elzbieta Galezowska Joanna Kosman Agnieszka Stepien Blazej Rubis Maria Rybczynska Bernard Juskowiak |
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Institution: | (1) Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, Przybyszewskiego 49, 60-355 Poznan, Poland;(2) Department of Clinical Immunology, Poznan University of Medical Sciences, Rokietnicka 5d, 60-806 Poznan, Poland;(3) Laboratory of Analytical Chemistry, Faculty of Chemistry, Adam Mickiewicz University in Poznan, Grunwaldzka 6, 60-780 Poznan, Poland;(4) Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, ul. Święcickiego 6, 60-781 Poznan, Poland; |
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Abstract: | G-quadruplexes are a family of DNA secondary structures resulting from the folding of a guanine-rich sequence. Targeting quadruplexes
by small molecules is an approach that is currently being studied with the aim of exploring their biological roles and developing
new anti-cancer agents. There is evidence that the formation of G4 structures by telomeric DNA can be used to inhibit the
enzyme activity of telomerase, and thereby to activate the pathway to senescence in tumour cells. It was previously shown
that the papaverine oxidation products 6a,12a-diazadibenzo-a,g]fluorenylium derivative (ligand I) and 2,3,9,10-tetramethoxy-12-oxo-12H-indolo2,1-a]isoquinolinium chloride (ligand II) bind to G-quadruplex representing the human telomeric sequence. These ligands possess the ability to inhibit telomerase
and polymerase action at the micromolar level. Here we report a DNA binding study on these two ligands and a new derivative
2-(2-carboxy-4,5-dimethoxyphenyl0-6,7-dimethoxyisoquiloliniuminner salt (ligand III) in order to evaluate their binding selectivity to samples of nucleic acids (ssDNA, dsDNA, triplexes, and quadruplexes).
Simultaneous investigations on several DNA-ligand complexes carried out using an equilibrium dialysis approach revealed pronounced
binding selectivity of ligand I and ligand II to tetraplex DNA structures over the doublestranded DNA forms. |
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