DNA Sequence Preference and Adduct Orientation of Pyrrolo[2,1-c][1,4]benzodiazepine Antitumor Agents.

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'-dir

SUBMITTER: Rahman KM 

PROVIDER: S-EPMC4007893 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature