title: Rapid and efficient hybridization-triggered crosslinking within a DNA duplex by an oligodeoxyribonucleotide bearing a conjugated cyclopropapyrroloindole.
abstract: The antitumor antibiotic CC-1065 binds in the minor groove of double-stranded DNA, and the cyclopropapyrroloindole (CPI) subunit of the drug alkylates adjacent adenines at their N-3 position. We have attached racemic CPI to oligodeoxyribonucleotides (ODNs) via a terminal phosphorothioate at either the 3'- or 5'-end of the ODNs. These conjugates were remarkably stable in aqueous solution at neutral pH even in the presence of strong nucleophiles. When a 3'-CPI-ODN conjugate was hybridized to a complementary DNA strand at 37 degrees C, the CPI moiety alkylated nearby adenine bases of the complement efficiently and rapidly, with a half-life of a few minutes. The 4'-CPR- ODN conjugate showed very little reactivity within the duplex. CPI-ODN conjugates should be highly effective sequence-specific inhibitors of single-stranded viral DNA replication or gene selective inhibitors of transcription initiation.
authors.affiliation: Epoch Pharmaceuticals, Inc., Bothell, WA 98021, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Lukhtanov
authors.forename: M A
authors.initials: MA
authors.lastname: Podyminogin
authors.forename: I V
authors.initials: IV
authors.lastname: Kutyavin
authors.forename: R B
authors.initials: RB
authors.lastname: Meyer
authors.forename: H B
authors.initials: HB
authors.lastname: Gamper
mesh_terms: D000478:Alkylation; D001483:Base Sequence; D003432:Cross-Linking Reagents; D004247:DNA / Q000378:metabolism*; D007211:Indoles / Q000378:metabolism*; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000378:metabolism*
chemical_list: D003432:Cross-Linking Reagents; D007211:Indoles; D009838:Oligodeoxyribonucleotides; D004247:DNA