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DNA sequence preference and adduct orientation of pyrrolo[2,1- c ][1,4]benzodiazepine antitumor agents

Rahman, KM; Vassoler, H; James, CH; Thurston, DE; (2010) DNA sequence preference and adduct orientation of pyrrolo[2,1- c ][1,4]benzodiazepine antitumor agents. ACS Medicinal Chemistry Letters , 1 (8) pp. 427-432. 10.1021/ml100131b.

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Abstract

The pyrrolobenzodiazepines (PBDs) are covalent DNA minor-groove binding agents with a reported preference for binding to 5′-Pu-G-Pu sequences with their A rings oriented toward the 3′-end of the covalently modified DNA strand. Using HPLC/MS methodology and a range of designed hairpin-forming 17-mer oligonucleotides, the kinetics of reaction of a bis-pyrrole PBD conjugate (GWL-78, 2) has been evaluated with eight isomeric oligonucleotides, each containing a single PBD binding site in one of two locations. The PBD-binding base pair triplets were designed to include every possible combination of A and T bases adjacent to the covalently reacting guanine. Contrary to expectations, 2 reacted most rapidly with TGT and TGA sequences, and adducts were observed to form in both the 3′- and the 5′-directions. Molecular modeling studies revealed that for 3′-oriented adducts, this preference could be explained by formation of a hydrogen bond between the N10-H of the PBD and the oxygen of the C2-carbonyl of a thymine base on the 3′-side of the covalently bound guanine. For 5′-adducts, an analogous PBD N10-H hydrogen bond may form instead to the N3 of an equivalent adenine on the opposite strand. © 2010 American Chemical Society.

Type: Article
Title: DNA sequence preference and adduct orientation of pyrrolo[2,1- c ][1,4]benzodiazepine antitumor agents
DOI: 10.1021/ml100131b
URI: http://discovery.ucl.ac.uk/id/eprint/1363997
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