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Design, Synthesis, and Biophysical and Biological Evaluation of a Series of Pyrrolobenzodiazepine−Poly(N-methylpyrrole) Conjugates

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journal contribution
posted on 07.09.2006, 00:00 by Geoff Wells, Christopher R. H. Martin, Philip W. Howard, Zara A. Sands, Charles A. Laughton, Arnaud Tiberghien, Chi Kit Woo, Luke A. Masterson, Marissa J. Stephenson, John A. Hartley, Terence C. Jenkins, Steven D. Shnyder, Paul M. Loadman, Michael J. Waring, David E. Thurston
A novel series of methyl ester-terminated C8-linked pyrrolobenzodiazepine (PBD)−poly(N-methylpyrrole) conjugates (50af) has been synthesized and their DNA interaction evaluated by thermal denaturation, DNA footprinting, and in vitro transcription stop assays. The synergistic effect of attaching a PBD unit to a polypyrrole fragment is illustrated by the large increase in DNA binding affinity (up to 50-fold) compared to the individual PBD and pyrrole components. 50af were found to bind mainly to identical DNA sequences but with apparent binding site widths increasing with molecular length and the majority of sites conforming to the consensus motif 5'-XGXWz (z = 3 ± 1; W = A or T; X = any base but preferably a purine). They also provided robust sequence-selective blockade of transcription at sites corresponding approximately to their DNA footprints. 50af were shown to have good cellular/nuclear penetration properties, and a degree of correlation between cytotoxicity and DNA-binding affinity was observed.