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¹ Institut National de la Santé et de la Recherche Médicale U-524 et Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, Institut de Recherches sur le Cancer de Lille, Lille, France; ² Biospectroscopy and Physical Chemistry Unit, University of Liege, Sart-Tilman, Liege, Belgium; ³ Laboratoire de Pharmacognosie, Université René Descartes (Paris 5), Centre National de la Recherche Scientifique UMR8638, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France; and ⁴ Division Recherche Cancérologie, Institut de Recherches Servier, Croissy sur Seine, France

Requests for reprints: Marie-Hélène David-Cordonnier, Institut National de la Santé et de la Recherche Médicale U-524, Institut de Recherches sur le Cancer de Lille, Place de Verdun, 59045 France. Phone: 33-320-16-92-20; Fax: 33-320-16-92-29. E-mail: david{at}lille.inserm.fr

The majority of DNA-binding small molecules known thus far stabilize duplex DNA against heat denaturation. A high, drug-induced increase in the melting temperature (T_m) of DNA is generally viewed as a good criterion to select DNA ligands and is a common feature of several anticancer drugs such as intercalators (e.g., anthracyclines) and alkylators (e.g., ecteinascidin 743). The reverse situation (destabilization of DNA to facilitate its denaturation) may be an attractive option for the identification of therapeutic agents acting on the DNA structure. We have identified the tumor-active benzoacronycine derivative S23906-1 [(±)-cis-1,2-diacetoxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2]acridin-7-one] as a potent DNA alkylating agent endowed with a helicase-like activity. Using complementary molecular approaches, we show that covalent binding to DNA of the diacetate compound S23906-1 and its monoacetate analogue S28687-1 induces a marked destabilization of the double helix with the formation of alkylated ssDNA. The DNA-bonding properties and effects on DNA structure of a series of benzoacronycine derivatives, including the dicarbamate analogue S29385-1, were studied using complementary biochemical (electromobility shift assay, nuclease S1 mapping) and spectroscopic (fluorescence and T_m measurements) approaches. Alkylation of guanines in DNA by S28687-1 leads to a local denaturation of DNA, which becomes susceptible to cleavage by nuclease S1 and significantly decreases the T_m of DNA. The drug also directly alkylates single-strand DNA, but mass spectrometry experiments indicate that guanines in duplexes are largely preferred over single-stranded structures. This molecular study expands the repertoire of DNA-binding mechanisms and provides a new dimension for DNA recognition by small molecules.

Key Words: DNA alkylation • acronycine • anticancer drug • drug-DNA recognition • helicase activity

Grant support: Association pour la Recherche sur le Cancer and Institut de Recherches sur le Cancer de Lille grants (C. Bailly) and a fellowship (M-H. David-Cordonnier).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 9/14/04; revised 10/19/04; accepted 11/ 8/04.