Wang, Yong-Dong and Dzieglielewski, Jaroslaw and Chang, Aileen Y. and Dervan, Peter B. and Beerman, Terry A. (2002) Cell-free and Cellular Activities of a DNA Sequence Selective Hairpin Polyamide-CBI Conjugate. Journal of Biological Chemistry, 277 (45). pp. 42431-42437. ISSN 0021-9258. http://resolver.caltech.edu/CaltechAUTHORS:WANjbc02
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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.
|Additional Information:||Copyright © 2002 by the American Society for Biochemistry and Molecular Biology. Received for publication, July 17, 2002, and in revised form, August 22, 2002. Originally published In Press as doi:10.1074/jbc.M207179200 on August 23, 2002. We thank Loretta Gawron for technical assistance and Drs. Marry M. McHugh and Christine M. White from Roswell Park Cancer Institute for critical reading of this manuscript. MDA435/LCC6 wild type and MDA435/LCC6 MDR multidrug-resistant cell lines were generously provided by Dr. R. Bernacki from Roswell Park Cancer Institute. This study was supported in part by National Institutes of Health Grants CA80939 and CA16056 (to T.A.B.) and GM27681 (to P.B.D.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. [A.Y.C. was] [s]upported by a National Research Service Award.|
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