Mapping Drug Interactions at the Covalent Topoisomerase II-DNA Complex by Bisantrene/Amsacrine Congeners*

To identify structural determinants for the sequence-specific recognition of covalent topoisomerase II-DNA complexes by anti-cancer drugs, we investigated a number of bisantrene congeners, including a 10-azabioisoster, bearing one or two 4,5-dihydro-1H-imidazol-2-yl hydrazone side chains at positions 1, 4, or 9 of the anthracene ring system. The studied bisantrene/amsacrine (m-AMSA) hybrid and bisantrene isomers were able to poison DNA topoisomerase II with an intermediate activity between those of bisantrene and m-AMSA. Moving the side chain from the central to a lateral ring (from C-9 to C-1/C-4) only slightly modified the drug DNA affinity, whereas it dramatically affected local base preferences of poison-stimulated DNA cleavage. In contrast, switching the planar aromatic systems of bisantrene andm-AMSA did not substantially alter the sequence specificity of drug action. A computer-assisted steric and electrostatic alignment analysis of the test compounds was in agreement with the experimental data, since a common pharmacophore was shared by bisantrene,m-AMSA, and 9-substituted analogs, whereas the 1-substituted isomer showed a radically changed pharmacophoric structure. Thus, the relative space occupancy and electron distribution of putative DNA binding (aromatic rings) and enzyme binding (side chains) moieties are fundamental in directing the specific action of topoisomerase II poisons and in determining the poison pharmacophore.

[1]  M. Palumbo.  Advances in DNA Sequence Specific Agents , 1998 .

[2]  G. Capranico,et al.  Synthesis, DNA-damaging and cytotoxic properties of novel topoisomerase II-directed bisantrene analogues. , 1998, Bioorganic & medicinal chemistry letters.

[3]  M. Palumbo.  Introduction to DNA sequence-specific agents , 1998 .

[4]  C. Dykes,et al.  Human genome project Europe. , 1997, Trends in pharmacological sciences.

[5]  Y. Pommier.  DNA Topoisomerase II Inhibitors , 1997 .

[6]  B. Teicher.  Cancer Therapeutics: Experimental And Clinical Agents , 1997, Nature Medicine.

[7]  F. Zunino,et al.  Drug sensitivity and sequence specificity of human recombinant DNA topoisomerases IIalpha (p170) and IIbeta (p180). , 1996, Molecular pharmacology.

[8]  W. Denny,et al.  Molecular origins of selectivity in the interaction of amsacrine-4-carboxamide with GC-rich sequences in DNA. , 1996, Anti-cancer drug design.

[9]  N. Osheroff,et al.  Topoisomerase Poisons: Harnessing the Dark Side of Enzyme Mechanism (*) , 1995, The Journal of Biological Chemistry.

[10]  K. Kohn,et al.  Interaction of an alkylating camptothecin derivative with a DNA base at topoisomerase I-DNA cleavage sites. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[11]  G. Capranico,et al.  Topoisomerase II DNA cleavage stimulation, DNA binding activity, cytotoxicity, and physico-chemical properties of 2-aza- and 2-aza-oxide-anthracenedione derivatives. , 1995, Molecular pharmacology.

[12]  F. Zunino,et al.  Base sequence determinants of amonafide stimulation of topoisomerase II DNA cleavage. , 1995, Nucleic acids research.

[13]  K. Kreuzer,et al.  Localization of an aminoacridine antitumor agent in a type II topoisomerase-DNA complex. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[14]  I. Hickson,et al.  Structure and function of type II DNA topoisomerases. , 1994, The Biochemical journal.

[15]  F. Zunino,et al.  Conformational drug determinants of the sequence specificity of drug-stimulated topoisomerase II DNA cleavage. , 1994, Journal of molecular biology.

[16]  K. Kohn,et al.  Distribution of topoisomerase II cleavage sites in simian virus 40 DNA and the effects of drugs. , 1991, Journal of molecular biology.

[17]  K. Kohn,et al.  Local base sequence preferences for DNA cleavage by mammalian topoisomerase II in the presence of amsacrine or teniposide. , 1991, Nucleic acids research.

[18]  K W Kohn,et al.  Effect of local DNA sequence on topoisomerase I cleavage in the presence or absence of camptothecin. , 1991, The Journal of biological chemistry.

[19]  N. Osheroff,et al.  Catalytic function of DNA topoisomerase II , 1991, BioEssays : news and reviews in molecular, cellular and developmental biology.

[20]  B. Baguley.  DNA intercalating anti-tumour agents. , 1991, Anti-cancer drug design.

[21]  K. Kohn,et al.  Local sequence requirements for DNA cleavage by mammalian topoisomerase II in the presence of doxorubicin. , 1990, Nucleic acids research.

[22]  M. Karol,et al.  DNA binding by antitumor anthracene derivatives. , 1990, Journal of medicinal chemistry.

[23]  F. Zunino,et al.  Evidence of DNA topoisomerase II-dependent mechanisms of multidrug resistance in P388 leukemia cells. , 1990, Molecular pharmacology.

[24]  L. Liu,et al.  DNA topoisomerase poisons as antitumor drugs. , 1989, Annual review of biochemistry.

[25]  B. Pullman,et al.  Energetics and stereochemistry of DNA complexation with the antitumor AT specific intercalators tilorone and m-AMSA. , 1988, Nucleic acids research.

[26]  Warren J. Hehre,et al.  AB INITIO Molecular Orbital Theory , 1986 .

[27]  Eamonn F. Healy,et al.  Development and use of quantum mechanical molecular models. 76. AM1: a new general purpose quantum mechanical molecular model , 1985 .

[28]  P. V. von Hippel,et al.  Theoretical aspects of DNA-protein interactions: co-operative and non-co-operative binding of large ligands to a one-dimensional homogeneous lattice. , 1974, Journal of molecular biology.