Issue 5, 2011

Observation of the reversibility of a covalent pyrrolobenzodiazepine (PBD) DNA adduct by HPLC/MS and CD spectroscopy

Abstract

Pyrrolobenzodiazepines (PBDs) are sequence-selective DNA minor-groove binding agents that covalently bond to guanine with a reported preference for Pu-G-Pu sequences (Pu = Purine). Using HPLC/MS and Circular Dichroism (CD) methodologies, we have established for the first time that the aminal bond formed between PBD molecules and DNA is reversible. Furthermore, we have shown that while the rate of aminal bond cleavage does not depend on the sequence preference of a PBD molecule for a particular binding site, the rate of re-formation of the PBD-DNA adduct does. We have also shown that the PBD anthramycin (2) appears to be an exception to this rule in that, during cleavage from the DNA, its C-ring aromatizes and it cannot then re-attach due to a loss of electrophilicity at the C11-position. Although the C-ring aromatization of anthramycin has been previously reported to occur in the absence of DNA and after treatment with trifluoroacetic acid (TFA), in this case no pH lowering was required, with the DNA itself appearing to catalyse the process.

Graphical abstract: Observation of the reversibility of a covalent pyrrolobenzodiazepine (PBD) DNA adduct by HPLC/MS and CD spectroscopy

Supplementary files

Article information

Article type
Paper
Submitted
21 Sep 2010
Accepted
12 Nov 2010
First published
21 Jan 2011

Org. Biomol. Chem., 2011,9, 1632-1641

Observation of the reversibility of a covalent pyrrolobenzodiazepine (PBD) DNA adduct by HPLC/MS and CD spectroscopy

K. M. Rahman, C. H. James and D. E. Thurston, Org. Biomol. Chem., 2011, 9, 1632 DOI: 10.1039/C0OB00762E

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