Pyrrolobenzodiazepines (PBDs) do not bind to DNA G-quadruplexes

PloS One
Khondaker M RahmanDavid E Thurston

Abstract

The pyrrolo[2,1-c][1,4] benzodiazepines (PBDs) are a family of sequence-selective, minor-groove binding DNA-interactive agents that covalently attach to guanine residues. A recent publication in this journal (Raju et al, PloS One, 2012, 7, 4, e35920) reported that two PBD molecules were observed to bind with high affinity to the telomeric quadruplex of Tetrahymena glaucoma based on Electrospray Ionisation Mass Spectrometry (ESI-MS), Circular Dichroism, UV-Visible and Fluorescence spectroscopy data. This was a surprising result given the close 3-dimensional shape match between the structure of all PBD molecules and the minor groove of duplex DNA, and the completely different 3-dimensional structure of quadruplex DNA. Therefore, we evaluated the interaction of eight PBD molecules of diverse structure with a range of parallel, antiparallel and mixed DNA quadruplexes using DNA Thermal Denaturation, Circular Dichroism and Molecular Dynamics Simulations. Those PBD molecules without large C8-substitutents had an insignificant affinity for the eight quadruplex types, although those with large π-system-containing C8-substituents (as with the compounds evaluated by Raju and co-workers) were found to interact to some extent. Our molecular...Continue Reading

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Citations

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Methods Mentioned

BETA
NMR
Assay
FRET
Fluorescence

Related Concepts

Pyrrolobenzodiazepine
Benzodiazepines
Circular Dichroism, Vibrational
DNA, Double-Stranded
Pyrroles
Fluorescence Spectroscopy
Spectrometry, Mass, Electrospray Ionization
Fluorescence Resonance Energy Transfer
Guanine-Tetrads
DNA

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