1 Chapter 06 DNA Interactive Agents. 2 Copyright © 2014 Elsevier Inc. All rights reserved. FIGURE 6.1 DNA structure. Reproduced with permission from Alberts,

1

Chapter 06

DNA Interactive Agents

2Copyright © 2014 Elsevier Inc. All rights reserved.

FIGURE 6.1 DNA structure. Reproduced with permission from Alberts, B., Bray, D., Lewis, J., Raff, M., Roberts, K., and Watson, J.D. (1989). Molecular Biology of the Cell, 2nd ed., p. 99. Garland Publishing, New York. Copyright 1989 Garland Publishing.


FIGURE 6.2 Characteristic of DNA base pairs that causes formation of major and minor grooves


FIGURE 6.3 Major and minor grooves of DNA. With permission from Kornberg, A. (1980); From DNA Replication by Arthur Kornberg. Copyright ©1980 by W. H. Freeman and Company. Used with permission.


FIGURE 6.4 Hydrogen bonding sites of the DNA bases. D, hydrogen bond donor; A, hydrogen bond acceptor


FIGURE 6.5 Nonpolar nucleoside isosteres (6.4 and 6.5) of thymidine and adenosine, respectively, that base pair by non-hydrogen-bond interactions


FIGURE 6.6 Stages in the formation of the entire metaphase chromosome starting from duplex DNA. With permission from Alberts, B., (1994). Copyright ©1994 from Molecular Biology of the Cell, 3rd ed. By Bruce Alberts, Dennis Bray, Julian Lewis, Martin Raff, Keith Roberts and James D. Watson. Reproduced by permission of Routledge, Inc., part of The Taylor & Francis Group.


FIGURE 6.7 Artist rendition of the conversion of duplex DNA into chromatin fiber


FIGURE 6.8 Conversion of duplex DNA into supercoiled DNA


FIGURE 6.9 Catenane and knot catalog. Arrows indicate the orientation of the DNA primary sequence: a and b, singly linked catenanes; c and d, simplest knot, the trefoil; e–h, multiply interwound torus catenanes; i, right-handed torus knot with seven nodes; j, right-handed torus catenane with eight notes; k, right-handed twist knot with seven nodes; l, 6-noded knots composed of two trefoils. Adapted with permission from Wasserman, S. A. and Cozzarelli, N. R. Biochemical topology: applications to DNA recombination and replication. Science, 1986, 232, 952. Reprinted with permission from AAAS.


FIGURE 6.10 Visualization of trefoil DNA by electron microscopy. Reproduced with permission from Griffith J.D., Nash, H.A., Proc. Natl. Acad. Sci. USA 1985, 82, 3124.


FIGURE 6.11 Mechanisms of DNA topoisomerase-catalyzed reactions. Drawings produced by Professor Alfonso Mondragón, Department of Molecular Biosciences, Northwestern University.


FIGURE 6.12 Artist rendition of a possible mechanism for a topoisomerase I reaction. The colored sections are the topoisomerase, and the black lines are the double-stranded DNA. With permission from Champoux, J.J. (2010). With permission from the Annual Review of Biochemistry. Volume 70 ©2001 by Annual Reviews. www.annualreview.org.


FIGURE 6.13 Artist rendition of possible mechanisms of topoisomerase IA-catalyzed relaxation of (A) supercoiled DNA and (B) decatenation of a DNA catenane. From Li, Z.; Mondragon, A.; DiGate, R. J. The mechanism of IA topoisomerase-mediated DNA topological transformations. Mol. Cell 2001, 7, 301.


FIGURE 6.14 Computer graphics depictions of A-DNA, B-DNA, and Z-DNA. Reproduced with permission from the Jena Library of Biological Macromolecules, Institute of Molecular Biotechnology (IMB), Jena, Germany; http://jenalib.fli-leibniz.de/ Hühne R., Koch F. T., Sühnel, J. A comparative view at comprehensive information resources on three-dimensional structures of biological macromolecules. Brief Funct. Genomic Proteomic 2007, 6(3), 220–239.


FIGURE 6.15 (A) Molecular model of a nucleosome. (B) Cutaway view of the nucleosome with the histones in the center and duplex DNA wrapped around them. With permission from Luger, K. (1977). Reprinted with permission from Macmillan Publishers Ltd: Nature 1993, 398, 251–260.


FIGURE 6.16 Schematic of how a drug could bind to DNA wrapped around histones in the nucleosome. Polach K. J. Mechanism of protein access to specific DNA sequences in chromatin: A dynamic equilibrium model for gene regulation. J. Mol Biol. 1995, 254, 130.


FIGURE 6.17 Schematic of three types of reversible DNA binders. A, external electrostatic binder; B, groove binder; C, intercalator. In B and C, the pink bar represents the drug. Reproduced with permission from Blackburn G. M., Gait M. J., Eds. Nucleic Acids in Chemistry and Biology, 2nd ed., 1996; p. 332. By permission of Oxford University Press.


FIGURE 6.18 Model showing interaction of netropsin (colored ball model) with double helical DNA (colored stick model). The 2D structure of netropsin (6.8) is also shown. Image created by JanLipfert from crystallographic coordinates deposited in the Protein Data Bank, accession code 101D.


FIGURE 6.19 Intercalation of ethidium bromide into B-DNA


FIGURE 6.20 X-ray structure of a 1:2 complex of dactinomycin with d(GC). Reprinted from Journal of Molecular Biology, Vol. 68, “Stereochemistry of actinomycin binding to DNA. II. Detailed molecular model of actinomycin DNA complex and its implications”, pp. 26–34. Copyright. 1972 Academic Press, with permission from Elsevier.


FIGURE 6.21 X-ray structure of daunorubicin intercalated into an oligonucleotide. Quigley, G. S.;Wang, A.; Ughetto, G.; Van der Marel, G.; Van Boom, J. H.; Rich, A. Molecular structure of an anticancer drug-DNA complex: Daunomycin plus d(CpGpTpApCpG). Proc. Natl. Acad. Sci. USA 1980, 77, p. 7206. Reprinted with permission from Dr. C. J. Quigley.


FIGURE 6.22 General structure of bis-quinoxaline intercalators


SCHEME 6.1 DNA topoisomerase-catalyzed strand cleavage to cleavable complexes


SCHEME 6.2 Nucleophilic substitution mechanisms


SCHEME 6.3 Alkylations by nitrogen mustards


SCHEME 6.4 Depurination of N-7 alkylated guanines in DNA


SCHEME 6.5 Interstrand cross-links of abasic sites in duplex DNA by reaction with guanine


SCHEME 6.6 Proposed mechanism for DNA alkylation by fasicularin


SCHEME 6.7 Reaction of nucleophiles with 4-spirocyclopropylcyclohexadienone


SCHEME 6.8 Stabilization of the spirocyclopropylcyclohexadienone by nitrogen conjugation


SCHEME 6.9 N-3 adenine alkylation by CC-1065 and related compounds


SCHEME 6.10 Decomposition of N-methyl-N-nitrosourea


SCHEME 6.11 Deuterium labeling experiment to determine mechanism of activation of nitrosoureas


SCHEME 6.12 Mechanism proposed for cross-linking of DNA by (2-chloroethyl)nitrosoureas


SCHEME 6.13 Alternative mechanism for the cross-linking of DNA by (2-chloroethyl)nitrosoureas


SCHEME 6.14 Mechanism for the methylation of DNA by dacarbazine


SCHEME 6.15 Mechanism for the bioactivation of mitomycin C and alkylation of DNA


SCHEME 6.16 Bioreductive monoalkylating agents


SCHEME 6.17 Bioreductive bis-alkylating agents


SCHEME 6.18 Model reaction for the mechanism of activation of leinamycin


SCHEME 6.19 Mechanism for DNA alkylation by leinamycin


SCHEME 6.20 Mechanism for hydrodisulfide activation of molecular oxygen to cause oxidative DNA damage


SCHEME 6.21 Electron transfer mechanism for DNA damage by anthracyclines


SCHEME 6.22 Anthracycline semiquinone generation of hydroxyl radicals


SCHEME 6.23 Conversion of iron chelator prodrug 6.70 into iron chelator 6.71


SCHEME 6.24 Cycle of events involved in DNA cleavage by bleomycin (BLM)


SCHEME 6.25 Alternative mechanisms for base propenal formation and DNA strand scission by activated bleomycin: (A) Modified Criegee mechanism and (B) Grob fragmentation mechanism


SCHEME 6.26 Mechanism for formation of hydroxyl radicals by tirapazamine


SCHEME 6.27 Mechanism for DNA-strand cleavage by tirapazamine


SCHEME 6.28 Activation of esperamicins and calicheamicins


SCHEME 6.29 Reductive mechanism for activation of dynemicin A


SCHEME 6.30 Nucleophilic mechanism for activation of dynemicin A


SCHEME 6.31 Activation of zinostatin by thiols


SCHEME 6.32 Polar addition reaction to deactivate zinostatin


SCHEME 6.33 DNA-strand scission by activated zinostatin and other members of the enediyne antibiotics. NCS, neocarzinostatin (Zinostatin)


SCHEME 6.34 Catalytic antibody-catalyzed conversion of an enediyne into a quinone via oxygenation of the corresponding benzene biradical


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Table 6.1

1 Chapter 06 DNA Interactive Agents. 2 Copyright © 2014 Elsevier Inc. All rights reserved. FIGURE 6.1 DNA structure. Reproduced with permission from Alberts,

Documents

supercoiled dna slide

dna replication

dna recombination

dna bases

dna structure

conversion of duplex

minor grooves of dna

visualization of trefoil