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Nucleic Acids Research, 2003, Vol. 31, No. 4 1208-1215
© 2003 Oxford University Press

DNA crosslinking and biological activity of a hairpin polyamide–chlorambucil conjugate

Yong-Dong Wang, Jaroslaw Dziegielewski, Nicholas R. Wurtz1, Barbara Dziegielewska, Peter B. Dervan1 and Terry A. Beerman*

Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA and 1 Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA

*To whom correspondence should be addressed. Tel: +1 716 845 3443; Fax: +1 716 845 1575; Email: terry.beerman{at}roswellpark.org

A prototype of a novel class of DNA alkylating agents, which combines the DNA crosslinking moiety chlorambucil (Chl) with a sequence-selective hairpin pyrrole–imidazole polyamide ImPy-ß-ImPy-{gamma}-ImPy-ß-Dp (polyamide 1), was evaluated for its ability to damage DNA and induce biological responses. Polyamide 1-Chl conjugate (1-Chl) alkylates and interstrand crosslinks DNA in cell-free systems. The alkylation occurs predominantly at 5'-AGCTGCA-3' sequence, which represents the polyamide binding site. Conjugate-induced lesions were first detected on DNA treated for 1 h with 0.1 µM 1-Chl, indicating that the conjugate is at least 100-fold more potent than Chl. Prolonged incubation allowed for DNA damage detection even at 0.01 µM concentration. Treatment with 1-Chl decreased DNA template activity in simian virus 40 (SV40) in vitro replication assays. 1-Chl inhibited mammalian cell growth, genomic DNA replication and cell cycle progression, and arrested cells in the G2/M phase. Moreover, cellular effects were observed at 1-Chl concentrations similar to those needed for DNA damage in cell-free systems. Neither of the parent compounds, unconjugated Chl or polyamide 1, demonstrated any cellular activity in the same concentration range. The conjugate molecule 1-Chl possesses the sequence-selectivity of a polyamide and the enhanced DNA reactivity of Chl.


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