Cell-free and Cellular Activities of a DNA Sequence Selective Hairpin Polyamide-CBI Conjugate

Alkylating agents are generally highly reactive with DNA but demonstrate limited DNA sequence selectivity. In contrast, synthetic pyrrole-imidazole polyamides recognize specific DNA sequences with high affinity but are unable to permanently damage DNA. An eight-ring hairpin polyamide conjugated to t...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-11, Vol.277 (45), p.42431-42437
Main Authors: Wang, Yong-Dong, Dziegielewski, Jaroslaw, Chang, Aileen Y, Dervan, Peter B, Beerman, Terry A
Format: Article
Language:English
Subjects:
Alkylating Agents - chemistry
Alkylating Agents - pharmacology
Base Sequence
Breast Neoplasms
Cell Cycle - drug effects
Cell Division - drug effects
DNA - chemistry
DNA Damage
DNA, Viral - chemistry
DNA, Viral - drug effects
Female
Humans
Indoles - chemical synthesis
Indoles - chemistry
Indoles - pharmacology
Nucleic Acid Conformation
Nylons
Oligodeoxyribonucleotides - chemistry
Pyrroles - chemical synthesis
Pyrroles - chemistry
Pyrroles - pharmacology
Simian virus 40 - genetics
Tumor Cells, Cultured
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Summary:Alkylating agents are generally highly reactive with DNA but demonstrate limited DNA sequence selectivity. In contrast, synthetic pyrrole-imidazole polyamides recognize specific DNA sequences with high affinity but are unable to permanently damage DNA. An eight-ring hairpin polyamide conjugated to the alkylating moiety cyclopropylpyrroloindole, related to the natural product CC-1065, affords a conjugate 1-CBI (polyamide 1-CBI (1-(chloromethyl)-5-hydroxyl-1,2-dihydro-3 H -benz[ e ]indole) conjugate), which binds to specific sequences in the minor groove of DNA and alkylates a single adenine flanking the polyamide binding site. In this study, we show that 1-CBI alkylates DNA in both plasmid and intracellular minichromosomal form and inhibits DNA replication under both cell-free and cellular conditions. In addition, it inhibits cell growth and arrests cells in the G 2 /M phase of the cell cycle.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M207179200