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 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-3H-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 G2/M phase of the cell cycle.
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Yong-Dong
YD
Wang
Jaroslaw
J
Dziegielewski
Aileen Y
AY
Chang
Peter B
PB
Dervan
Terry A
TA
Beerman
D000477:Alkylating Agents / Q000737:chemistry* / Q000494:pharmacology; D001483:Base Sequence; D001943:Breast Neoplasms; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000737:chemistry*; D004249:DNA Damage; D004279:DNA, Viral / Q000737:chemistry / Q000187:drug effects; D005260:Female; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009690:Nucleic Acid Conformation; D009757:Nylons; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013539:Simian virus 40 / Q000235:genetics; D014407:Tumor Cells, Cultured
D000477:Alkylating Agents; D004279:DNA, Viral; D007211:Indoles; D009757:Nylons; D009838:Oligodeoxyribonucleotides; D011758:Pyrroles; C470729:polyamide 1-(chloromethyl)-5-hydroxyl-1,2-dihydro--3H-benz(e)indole conjugate; D004247:DNA