Molecular Recognition of Parallel DNA Quadruplex d(TTAGGGT)4 by Mitoxantrone: Binding with 1:2 Stoichiometry Leading to Thermal Stabilization and Telomerase Inhibition.
Chembiochem
; 17(7): 554-60, 2016 Apr 01.
Article
em En
| MEDLINE
| ID: mdl-26762575
ABSTRACT
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.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Mitoxantrona
/
Telomerase
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Quadruplex G
Limite:
Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article