Rapid and efficient hybridization-triggered crosslinking within a DNA duplex by an oligodeoxyribonucleotide bearing a conjugated cyclopropapyrroloindole.
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.
Lukhtanov
E A
EA
Epoch Pharmaceuticals, Inc., Bothell, WA 98021, USA.
Podyminogin
M A
MA
Kutyavin
I V
IV
Meyer
R B
RB
Gamper
H B
HB
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*
D003432:Cross-Linking Reagents; D007211:Indoles; D009838:Oligodeoxyribonucleotides; D004247:DNA