title: Pyrrolobenzodiazepines (PBDs) do not bind to DNA G-quadruplexes.
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 dynamics simulations support the likelihood that molecules of this type, including those examined by Raju and co-workers, interact with quadruplex DNA through their C8-substituents rather than the PBD moiety itself. It is important for the literature to be clear on this matter, as the mechanism of action of these agents will be under close scrutiny in the near future due to the growing number of PBD-based agents entering the clinic as both single-agents and as components of antibody-drug conjugates (ADCs).
authors.affiliation: Department of Pharmacy, Institute of Pharmaceutical Science, King's College London, London, United Kingdom.
authors.forename: Khondaker M
authors.initials: KM
authors.lastname: Rahman
authors.affiliation: Department of Pharmacy, Institute of Pharmaceutical Science, King's College London, London, United Kingdom.
authors.forename: David B
authors.initials: DB
authors.lastname: Corcoran
authors.affiliation: Department of Pharmacy, Institute of Pharmaceutical Science, King's College London, London, United Kingdom.
authors.forename: Tam T T
authors.initials: TT
authors.lastname: Bui
authors.affiliation: Department of Pharmacy, Institute of Pharmaceutical Science, King's College London, London, United Kingdom.
authors.forename: Paul J M
authors.initials: PJ
authors.lastname: Jackson
authors.affiliation: Department of Pharmacy, Institute of Pharmaceutical Science, King's College London, London, United Kingdom.
authors.forename: David E
authors.initials: DE
authors.lastname: Thurston
mesh_terms: D001569:Benzodiazepines / Q000737:chemistry*; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry*; D031541:Fluorescence Resonance Energy Transfer; D054856:G-Quadruplexes; D006801:Humans; D011758:Pyrroles / Q000737:chemistry*; D013050:Spectrometry, Fluorescence; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D011758:Pyrroles; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; D001569:Benzodiazepines; D004247:DNA