Observation of a dynamic equilibrium between DNA hairpin and duplex forms of covalent adducts of a minor groove binding agent.
A dynamic equilibrium between covalent 1:1 hairpin and 2:1 duplex DNA adducts of a pyrrolobenzodiazepine (PBD) minor groove binding agent () has been observed for the first time. The equilibrium, which establishes over 1 hour and must require unfolding of both types of adducts, is surprising given that PBDs normally require DNA minor groove structure for binding and take 24 hours for complete reaction with duplex DNA. The equilibrium is interesting from an energetics perspective due to the well known DNA stabilizing effect of PBDs. This observation could have significance for the in vitro and in vivo biological activity of PBDs, as DNA hairpin and loop structures are known to be important in cellular processes such as transcription and replication.
Rahman
Khondaker M
KM
Gene Targeted Drug Design Research Group, School of Pharmacy, University of London, 29/39 Brunswick Square, London, UK WC1N 1AX.
Mussa
Vanelssa
V
Narayanaswamy
Mathangi
M
James
Colin H
CH
Howard
Philip W
PW
Thurston
David E
DE
D001483:Base Sequence; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry* / Q000187:drug effects*; D018736:DNA Adducts / Q000737:chemistry* / Q000187:drug effects*; D009690:Nucleic Acid Conformation / Q000187:drug effects*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D018736:DNA Adducts; D011758:Pyrroles; D001569:Benzodiazepines; D004247:DNA