Linkers designed to intercalate the double helix greatly facilitate DNA alkylation by triplex-forming oligonucleotides carrying a cyclopropapyrroloindole reactive moiety

Triplex-forming oligonucleotides (TFOs) bind sequence-specifically in the major groove of double-stranded DNA. Cyclopropapyrroloindole (CPI), the electrophilic moiety that comprises the reactive subunit of the antibiotic CC-1065, gives hybridization-triggered alkylation at the N-3 position of adenin...

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Bibliographic Details
Published in:Nucleic acids research 1999-07, Vol.27 (14), p.2931-2937
Main Authors: Dempcy, Robert O., Kutyavin, Igor V., Mills, Alan G., Lukhtanov, Eugeny A., Meyer, Rich B.
Format: Article
Language:English
Subjects:
Acridines - chemistry
Acridines - metabolism
Adenine - chemistry
Adenine - metabolism
Alkylation
Base Sequence
Binding Sites
Cyclopropanes - metabolism
DNA - chemistry
DNA - genetics
DNA - metabolism
Drug Design
Indoles - metabolism
Intercalating Agents - metabolism
Leucomycins - chemistry
Models, Chemical
Nucleic Acid Conformation
Nucleic Acid Hybridization
Oligodeoxyribonucleotides - chemistry
Oligodeoxyribonucleotides - genetics
Oligodeoxyribonucleotides - metabolism
Substrate Specificity
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Summary:Triplex-forming oligonucleotides (TFOs) bind sequence-specifically in the major groove of double-stranded DNA. Cyclopropapyrroloindole (CPI), the electrophilic moiety that comprises the reactive subunit of the antibiotic CC-1065, gives hybridization-triggered alkylation at the N-3 position of adenines when bound in the minor groove of double-stranded DNA. In order to attain TFO-directed targeting of CPI, we designed and tested linkers to ‘thread’ DNA from the major groove-bound TFO to the minor groove binding site of CPI. Placement of an aromatic ring in the linker significantly enhanced the site-directed reaction, possibly due to a ‘threading’ mechanism where the aromatic ring is intercalated. All of the linkers containing aromatic rings provided efficient alkylation of the duplex target. The linker containing an acridine ring system, the strongest intercalator in the series, gave a small but clearly detectable amount of non-TFO-specific alkylation. An equivalent-length linker without an aromatic ring was very inefficient in DNA target alkylation.
ISSN:0305-1048
1362-4962
1362-4962
DOI:10.1093/nar/27.14.2931