Evidence for DNA phosphate backbone alkylation and cleavage by pyrrolo[1,2-a]benzimidazoles: small molecules capable of causing base-pair-specific phosphodiester bond hydrolysis.
This report presents evidence that a reduced pyrrolo[1,2-a]benzimidazole (PBI) cleaves DNA as a result of phosphate alkylation followed by hydrolysis of the resulting phosphate triester. The base-pair specificity of the phosphate alkylation results from Hoogsteen-type hydrogen bonding of the reduced PBI in the major groove at only A.T and G.C base pairs. Alkylated phosphates were detected by 31P NMR and the cleavage products were detected by 1H NMR and HPLC. Evidence is also presented that a reduced PBI interacts with DNA in the major groove rather than in the minor groove or by intercalation.
Department of Chemistry and Biochemistry, Arizona State University, Tempe 85287-1604, USA.
W G
WG
Schulz
R A
RA
Nieman
E B
EB
Skibo
D000477:Alkylating Agents / Q000737:chemistry*; D000478:Alkylation; D001562:Benzimidazoles / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry*; D004249:DNA Damage; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D010755:Organophosphates / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry*
D000477:Alkylating Agents; D001562:Benzimidazoles; D010755:Organophosphates; D011758:Pyrroles; D004247:DNA