Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 1, Issue 8, Pages 427-432Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ml100131b
Keywords
Pyrrolo[2,1-c][1,4]benzodiazepine (PBD); antitumor agents; GWL-78; DNA; minor-groove binder
Categories
Funding
- Commonwealth Commission [BDCA005/01]
- Spirogen Ltd. [GWL-78 (2)]
Ask authors/readers for more resources
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 rights 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available