Localized Chemical Reactivity in Double‐Stranded DNA Associated with the Intercalative Binding of Benzo[e]Pyridoindole and Benzo[g]Pyridoindole Triple‐Helix‐Stabilizing Ligands

Abstract

Footprinting with methidiumpropyl‐EDTA · FeII has been used to map the binding sites on duplex DNA of two closely related benzopyridoindole derivatives which selectively stabilize triple‐helical DNA–oligonucleotide complexes. Both ligands bind to many sites, including certain oligopurine · oligopyrimidine tracts, with a weak preference for some (but not all) sequences rich in A · T base pairs. This indifference to primary sequence, with evidence of binding to the commonly disfavoured (A)n· (T)ntracts, may at least partially explain why the ligands stabilize triplex structures composed of T · A · T pairings. Neither 3‐methoxy‐7H‐8‐methyl‐11‐[(3′amino)propylamino]benzo[e]pyrido[4, 3‐b]indole (BePI) nor 3‐methoxy‐7‐[3′‐diethylamino)propylamino]‐10–methyl‐11H‐benzo[g]pyrido[4,3‐b]indole (BgPI) affect the reaction of dimethyl sulphate or potassium tetrachloropalladinate with the N7 of purines in the major groove, but both enhance the reactivity of purines (mostly adenine residues) towards diethylpyrocarbonate, both proximal and distal to their identified binding sites. With potassium permanganate and osmium tetroxide/pyridine, probes for the accessibility of the 5,6 double bond of pyrimidine residues, BgPI has a more potent effect than BePI and, generally, the reaction with KMnO4 is more pronounced than that with OsO4. BgPI conspicuously potentiates the oxidation of pyrimidines in the triplet sequences 3′‐ATA, 3′‐GTA and 3′‐GCA, whereas BePI enhances the reactivity of OsO4 towards thymine in sequences 3′‐ATYR, with no effect on cytosine residues. Thus, despite their structural homology and common lack of specific sequence preferences, the two benzopyridoindole derivatives induce distinct conformational changes in duplex DNA, not just within the sites where footprints can be detected. Copyright © 1995, Wiley Blackwell. All rights reserved