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Molecular Recognition of Parallel DNA Quadruplex d(TTAGGGT)4 by Mitoxantrone: Binding with 1:2 Stoichiometry Leading to Thermal Stabilization and Telomerase Inhibition.

Authors: Sweta S. Tripathi, Tarikere Palakshan TP. Pradeep, Ritu R. Barthwal
Published: 02/16/2016, Chembiochem : a European journal of chemical biology


The interaction of the anthraquinone derivative mitoxantrone, a semisynthetic anti-cancer drug with two non-planar side chains, with heptamer G-quadruplex d(TTAGGGT)4 , which contains the human telomere DNA sequence, was evaluated by differential scanning calorimetry, fluorescence Job plotting, absorption, and NMR and CD spectroscopy. Binding led to thermal stabilization of DNA (ΔTm =13-20 °C). The spectra revealed that two mitoxantrone molecules bind externally at two sites of the DNA quadruplex as monomers, by partial insertion of the chromophore and side-chain interaction at the grooves. The inhibition of telomerase (IC50 =2 μm), as determined by a TRAP assay, can be attributed to thermal stabilization of the DNA quadruplex because of the interactions with mitoxantrone. The studies revealed highly specific molecular recognition between a ligand and a parallel-stranded G-quadruplex; this might serve as a platform for the rational design of new drugs.

© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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