Copper-Dependent Oxidative and Topoisomerase II-Mediated DNA Cleavage by a Netropsin/4′-(9-acridinylamino)methanesulfon-m-anisidide Combilexin

  1. Jean-Pierre Henichart1,
  2. Michael J. Waring2,
  3. Jean-Francois Riou3,
  4. William A. Denny4 and
  5. Christian Bailly5
  1. 1Institut de Chimie Pharmaceutique, Université de Lille II, 59006 Lille, France (J.-P.H.), 2Department of Pharmacology, University of Cambridge, Cambridge CB2 1QJ, UK (M.J.W.), 3Rhône-Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, 94403 Vitry sur Seine, France (J.-F.R.), 4Cancer Research Laboratory, University of Auckland School of Medicine, Auckland, New Zealand (W.A.D.), and 5Institut de Recherches sur le Cancer, Institut National de la Santé et de la Recherche Médicale Unité 124, 59045 Lille, France (C.B.)

    Abstract

    A conjugate molecule was synthesized by linking the DNA-intercalative antitumor drug 4′-(9-acridinylamino)methanesulfon-m-anisidide (mAMSA) via a 4-carboxamide side chain to a dipyrrolecarboxamide moiety structurally related to the minor groove-binding antibiotic netropsin. The molecule (netropsin/mAMSA) behaves as a threading intercalator. Its netropsin-like tail becomes located in the minor groove of the double helix and serves to drive the hybrid molecule preferentially to AT-rich sites on various DNA fragments as revealed by DNase I footprinting. The hybrid retains the susceptibility to copper-dependent oxidation characteristic of the parent mAMSA moiety as well as its ability to generate oxygen radicals, which can mediate DNA damage, mainly at cytidine and guanosine nucleotides. It also retains the property of stimulating the formation of cleavable complexes with DNA in the presence of topoisomerase II, but its netropsin-like moiety confers little or no influence on the reaction with topoisomerase I. Although netropsin/mAMSA is less potent than mAMSA at producing cleavable complexes with topoisomerase II, it promotes the appearance of cleavage sites at much the same nucleotide sequences as does the parent compound. The dipyrrolecarboxamide tail is not silent, however, since it modifies the concentration-dependence of cleavable complex formation.

    Footnotes

    • Send reprint requests to: Dr. Christian Bailly, Institut de Recherches sur le Cancer, INSERM Unité 124, Place de Verdun, 59045 Lille, France. E-mail:bailly{at}lille.inserm.fr

    • ↵1 E. De Clercq, unpublished observations.

    • This work was supported by research grants from Institut National de la Santé et de la Recherche Médicale (C.B.), Ligue Nationale Contre le Cancer (Comité du Nord) (C.B.), Association pour la Recherche sur le Cancer (C.B.), Cancer Research Campaign (M.J.W.), Wellcome Trust (M.J.W.), Association for International Cancer Research (M.J.W.), and Sir Halley Stewart Trust (M.J.W.).

    • Abbreviations:
      mAMSA
      4′-(9-acridinylamino)methanesulfon-m-anisidide (amsacrine)
      bp
      base-pair
      SDS
      sodium dodecyl sulfate
      NetAmsa
      netropsin-4′-(9-acridinylamino)methanesulfon-manisidide
      MPE
      methidiumpropyl-EDTA
      mAQDI
      N1′-methanesulfonyl-N4′-(9-acridinyl)-3′-methoxy-2′,5′-cyclohexadiene-1′,4′-diimine
      mAQI
      3′-methoxy-4′-(9-acridinyl-amino)-2′,5′-cyclohexodiene-1′-one
      • Received July 2, 1996.
      • Accepted October 20, 1996.
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    1. Molecular Pharmacology March 1, 1997 vol. 51 no. 3 448-461
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