1 Chapter 06 DNA Interactive Agents

2 Copyright © 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.

3 Copyright © 2014 Elsevier Inc. All rights reserved. FIGURE 6.2 Characteristic of DNA base pairs that causes formation of major and minor grooves

4 Copyright © 2014 Elsevier Inc. All rights reserved. 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.

5 Copyright © 2014 Elsevier Inc. All rights reserved. FIGURE 6.4 Hydrogen bonding sites of the DNA bases. D, hydrogen bond donor; A, hydrogen bond acceptor

6 Copyright © 2014 Elsevier Inc. All rights reserved. FIGURE 6.5 Nonpolar nucleoside isosteres (6.4 and 6.5) of thymidine and adenosine, respectively, that base pair by non-hydrogen-bond interactions

7 Copyright © 2014 Elsevier Inc. All rights reserved. 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.

8 Copyright © 2014 Elsevier Inc. All rights reserved. FIGURE 6.7 Artist rendition of the conversion of duplex DNA into chromatin fiber

9 Copyright © 2014 Elsevier Inc. All rights reserved. FIGURE 6.8 Conversion of duplex DNA into supercoiled DNA

10 Copyright © 2014 Elsevier Inc. All rights reserved. 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.

11 Copyright © 2014 Elsevier Inc. All rights reserved. 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.

12 Copyright © 2014 Elsevier Inc. All rights reserved. FIGURE 6.11 Mechanisms of DNA topoisomerase-catalyzed reactions. Drawings produced by Professor Alfonso Mondragón, Department of Molecular Biosciences, Northwestern University.

13 Copyright © 2014 Elsevier Inc. All rights reserved. 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.

14 Copyright © 2014 Elsevier Inc. All rights reserved. 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.

15 Copyright © 2014 Elsevier Inc. All rights reserved. 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; 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.

16 Copyright © 2014 Elsevier Inc. All rights reserved. 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.

17 Copyright © 2014 Elsevier Inc. All rights reserved. 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.

18 Copyright © 2014 Elsevier Inc. All rights reserved. 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 By permission of Oxford University Press.

19 Copyright © 2014 Elsevier Inc. All rights reserved. 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.

20 Copyright © 2014 Elsevier Inc. All rights reserved. FIGURE 6.19 Intercalation of ethidium bromide into B-DNA

21 Copyright © 2014 Elsevier Inc. All rights reserved. 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 Academic Press, with permission from Elsevier.

22 Copyright © 2014 Elsevier Inc. All rights reserved. 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 Reprinted with permission from Dr. C. J. Quigley.

23 Copyright © 2014 Elsevier Inc. All rights reserved. FIGURE 6.22 General structure of bis-quinoxaline intercalators

24 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.1 DNA topoisomerase-catalyzed strand cleavage to cleavable complexes

25 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.2 Nucleophilic substitution mechanisms

26 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.3 Alkylations by nitrogen mustards

27 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.4 Depurination of N-7 alkylated guanines in DNA

28 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.5 Interstrand cross-links of abasic sites in duplex DNA by reaction with guanine

29 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.6 Proposed mechanism for DNA alkylation by fasicularin

30 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.7 Reaction of nucleophiles with 4-spirocyclopropylcyclohexadienone

31 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.8 Stabilization of the spirocyclopropylcyclohexadienone by nitrogen conjugation

32 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.9 N-3 adenine alkylation by CC-1065 and related compounds

33 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.10 Decomposition of N-methyl-N-nitrosourea

34 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.11 Deuterium labeling experiment to determine mechanism of activation of nitrosoureas

35 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.12 Mechanism proposed for cross-linking of DNA by (2-chloroethyl)nitrosoureas

36 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.13 Alternative mechanism for the cross-linking of DNA by (2-chloroethyl)nitrosoureas

37 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.14 Mechanism for the methylation of DNA by dacarbazine

38 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.15 Mechanism for the bioactivation of mitomycin C and alkylation of DNA

39 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.16 Bioreductive monoalkylating agents

40 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.17 Bioreductive bis-alkylating agents

41 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.18 Model reaction for the mechanism of activation of leinamycin

42 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.19 Mechanism for DNA alkylation by leinamycin

43 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.20 Mechanism for hydrodisulfide activation of molecular oxygen to cause oxidative DNA damage

44 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.21 Electron transfer mechanism for DNA damage by anthracyclines

45 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.22 Anthracycline semiquinone generation of hydroxyl radicals

46 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.23 Conversion of iron chelator prodrug 6.70 into iron chelator 6.71

47 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.24 Cycle of events involved in DNA cleavage by ­bleomycin (BLM)

48 Copyright © 2014 Elsevier Inc. All rights reserved. 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

49 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.26 Mechanism for formation of hydroxyl radicals by tirapazamine

50 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.27 Mechanism for DNA-strand cleavage by tirapazamine

51 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.28 Activation of esperamicins and calicheamicins

52 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.29 Reductive mechanism for activation of dynemicin A

53 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.30 Nucleophilic mechanism for activation of dynemicin A

54 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.31 Activation of zinostatin by thiols

55 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.32 Polar addition reaction to deactivate zinostatin

56 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.33 DNA-strand scission by activated zinostatin and other members of the enediyne antibiotics. NCS, neocarzinostatin (Zinostatin)

57 Copyright © 2014 Elsevier Inc. All rights reserved. SCHEME 6.34 Catalytic antibody-catalyzed conversion of an enediyne into a quinone via oxygenation of the corresponding benzene biradical

58 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.1

59 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.2

60 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.3

61 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.4

62 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.5

63 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.6

64 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.7

65 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.8

66 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.9

67 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.10

68 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.11

69 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.12

70 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.13

71 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.14

72 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.15

73 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.16

74 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.17

75 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.18

76 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.19

77 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.20

78 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.21

79 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.22

80 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.23

81 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.24

82 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.25

83 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.26

84 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.27

85 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.28

86 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.29

87 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.30

88 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.31

89 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.32

90 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.33

91 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.34

92 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.35

93 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.36

94 Copyright © 2014 Elsevier Inc. All rights reserved. UnnFigure 6.37

95 Copyright © 2014 Elsevier Inc. All rights reserved. Table 6.1