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Sequence-selective binding of C8-conjugated pyrrolobenzodiazepines (PBDs) to DNA

Research output: Contribution to journalArticlepeer-review

Mohammad A. Basher, Khondaker Miraz Rahman, Paul J.M. Jackson, David E. Thurston, Keith R. Fox

Original languageEnglish
Pages (from-to)53-61
JournalBiophysical Chemistry
Volume230
Early online date1 Sep 2017
DOIs
Accepted/In press18 Aug 2017
E-pub ahead of print1 Sep 2017
PublishedNov 2017

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Abstract

DNA footprinting and melting experiments have been used to examine the sequence-specific binding of C8-conjugates of pyrrolobenzodiazepines (PBDs) and benzofused rings including benzothiophene and benzofuran, which are attached using pyrrole- or imidazole-containing linkers. The conjugates modulate the covalent attachment points of the PBDs, so that they bind best to guanines flanked by A/T-rich sequences on either the 5′- or 3′-side. The linker affects the binding, and pyrrole produces larger changes than imidazole. Melting studies with 14-mer oligonucleotide duplexes confirm covalent attachment of the conjugates, which show a different selectivity to anthramycin and reveal that more than one ligand molecule can bind to each duplex.

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