Sequence-specific DNA binding agents

The binding of antibiotics and drugs to DNA is a fast developing area of research with important applications in medicine, particularly the treatment of cancer. Sequence-specific DNA Binding Agents uniquely discusses key aspects of this topic, providing a novel perspective on the subject. Written by experts in the field, this book discusses diverse modes of binding of antibiotics and drugs to DNA, emphasising matters that are important or promising for cancer treatment. Chapters discuss established agents like actinomycin D but also look at novel drugs with strong potential in chemotherapy such as new topoisomerase inhibitors, telomerase inhibitors, peptide nucleic acids and triple helix-forming oligonucleotides. There are also sections discussing methodological advances including computational methods, slow kinetics, melting curve analysis and approaches to medicinal chemistry. Finally there is a section on RNA structure and its potential as a drug target. The book is ideal for researchers in industry and academia who require a comprehensive source of reference to this rapidly expanding subject.

David A. Rusling and Tom Brown and Keith R. FoxChristophe Marchand and Yves PommierNathalie Dias and Christian BaillyL. Marcus Wilhelmsson and Per Lincoln and Bengt NordenPeter E. NielsenDavid E. GravesJonathan B. Chaires and XiaochunFederico GagoStephen NeidleDaekyu Sun and Laurence H. HurleyAlexander Serganov and Dinshaw J. Patel

Chapter 1 DNA Recognition by Triple Helix Formation	p. 1
1.1 Introduction	p. 1
1.1.1 Triplets and Triplex Motifs	p. 1
1.2 Strategies to Increase Triplex Stability	p. 3
1.2.1 Sugar Modifications	p. 3
1.2.2 Addition of Positive Charges	p. 4
1.2.3 Backbone Modifications	p. 9
1.2.4 Base Stacking	p. 10
1.2.5 Triplex-Binding Ligands	p. 10
1.3 Overcoming the pH Dependency	p. 11
1.3.1 Pyrimidine Base Analogues	p. 12
1.3.2 Purine Base Analogues	p. 13
1.4 Recognition of Pyrimidine Interruptions	p. 14
1.4.1 Null Bases and Abasic Linkers	p. 14
1.4.2 Natural Bases	p. 15
1.4.3 Nucleotide Analogues for Recognizing Pyrimidine Interruptions	p. 16
1.4.4 Nucleotide Analogues for Recognizing both Partners of the Base Pair	p. 18
1.5 Mixed Sequence Recognition	p. 20
Acknowledgements	p. 22
References	p. 22
Chapter 2 Interfacial Inhibitors of Human Topoisomerase I	p. 29
2.1 Introduction	p. 29
2.2 Molecular Mechanism of Action of Drugs that Trap Top1 Cleavage Complexes	p. 33
2.2.1 Intercalation between the Base Pairs Flanking the Top1-Mediated DNA Break	p. 33
2.2.2 DNA Untwisting by Drugs at the Top1-Mediated DNA Cleavage Site	p. 35
2.2.3 Common Hydrogen-Bond Network for Top1 Inhibitors Bound in the Ternary Complex	p. 37
2.3 Generalization of the Interfacial Inhibitor Concept	p. 39
Acknowledgments	p. 41
References	p. 41
Chapter 3 Diversity of Topoisomerase I Inhibitors for Cancer Chemotherapy	p. 44
3.1 Introduction	p. 44
3.2 Camptothecins	p. 47
3.3 Indenoisoquinolines	p. 51
3.4 Benzimidazoles	p. 54
3.5 Indolocarbazoles	p. 54
3.6 Phenanthridines and Related Compounds	p. 56
3.7 Marine Alkaloids	p. 58
3.8 Plant Natural Products	p. 59
3.9 Conclusion	p. 60
References	p. 60
Chapter 4 Slow DNA Binding	p. 69
4.1 Introduction - Kinetics vs. Thermodynamics of DNA Binding	p. 69
4.2 Different DNA-Binding Modes - Different DNA-Binding Kinetics	p. 71
4.2.1 External Electrostatic Binding	p. 74
4.2.2 Groove Binding	p. 75
4.2.3 Intercalation	p. 76
4.2.4 Threading Intercalation	p. 77
4.3 Common Slow DNA Binders	p. 78
4.3.1 Actinomycin D	p. 78
4.3.2 Nogalamycin	p. 80
4.4 Ruthenium Complexes Exhibiting Slow DNA Binding Kinetics	p. 82
4.4.1 Bis-intercalating Ru-dimer [[Mu]-c4(cpdppz)[subscript 2] (phen)[subscript 4]Ru[subscript 2][superscript 4]+	p. 84
4.4.2 Semirigid Ru-dimer [[Mu]-11,11[prime]-bidppz)(x)[subscript 4]Ru[subscript 2]+ (x=phen or bipy)	p. 87
References	p. 91
Chapter 5 DNA Gene Targeting using Peptide Nucleic Acid (PNA)	p. 96
5.1 Introduction	p. 96
5.2 Duplex DNA Recognition in vitro	p. 97
5.3 PNA Conjugates	p. 99
5.4 Effect of PNA Binding on DNA Structure	p. 100
5.5 Cellular Gene Targeting	p. 101
5.6 Activation of Gene Transcription	p. 102
5.7 Gene-Targeted Repair	p. 102
5.8 Cellular Delivery and Bioavailability in vivo	p. 102
5.9 Prospects	p. 103
References	p. 103
Chapter 6 Actinomycin D: Sixty Years of Progress in Characterizing a Sequence-Selective DNA-Binding Agent	p. 109
6.1 Summary	p. 109
6.2 Introduction	p. 110
6.2.1 Historical Perspectives	p. 110
6.3 DNA-Binding Studies: The Early Years	p. 113
6.3.1 The Intercalation Model	p. 113
6.3.2 Sequence-Selectivity of Actinomycin D	p. 115
6.4 Characterization of the Actinomycin D-DNA Complex	p. 116
6.4.1 Role of Bases Flanking the Actinomycin D-Binding Site	p. 116
6.4.2 Promiscuity in the Sequence Selectivity of Actinomycin D	p. 118
6.5 Global vs. Microscopic Sequence-Recognition	p. 119
6.5.1 The Shuffling Hypothesis Revisited	p. 120
6.6 Structural Motifs as Actinomycin D Targets	p. 122
6.6.1 The Era of Single-Strand DNA Binding	p. 122
6.7 Conclusions	p. 125
Acknowledgments	p. 126
References	p. 126
Chapter 7 Thermal Denaturation of Drug-DNA Complexes: Tools and Tricks	p. Shi
7.1 Introduction	p. 130
7.2 Thermal Denaturation Tools	p. 131
7.2.1 Analysis of T[subscript m] Shifts in the Presence of Drug	p. 131
7.2.2 Obtaining Binding Enthalpy Values by DSC	p. 133
7.2.3 Modeling Melting Curves by McGhee's Algorithm	p. 136
7.2.4 Case Studies: Bisintercalating Anthracyclines and Echinomycin	p. 137
7.2.5 Summary: Advantages and Pitfalls	p. 142
7.3 Thermal Denaturation: New Tricks	p. 143
7.3.1 Melting Mixtures to Assess Sequence- and Structural-Selectivity	p. 143
7.3.2 Advantages and Prospects	p. 148
7.4 Summary	p. 148
Acknowledgments	p. 148
References	p. 148
Chapter 8 Computer Simulations of Drug-DNA interactions: A Personal Journey	p. 152
8.1 Introduction	p. 152
8.2 Minor Groove DNA Binders	p. 155
8.3 Natural Bifunctional Intercalators and Hoogsteen Base Pairing	p. 158
8.4 Bis-Intercalation of Echinomycin and Related Bifunctional Agents in Relation to Binding Sequence Preferences	p. 162
8.5 Binding Preferences of Synthetic Pyridocarbazole Bis-Intercalators	p. 167
8.6 Sequence Selectivity of Actinomycin D	p. 169
8.7 Binding of the Potent Antitumour Agent Trabectedin to DNA	p. 171
8.8 Lamellarins as Topoisomerase I Poisons	p. 176
8.9 Concluding Remarks	p. 179
Acknowledgements	p. 179
References	p. 179
Chapter 9 The Discovery of G-Quadruplex Telomere Targeting Drugs	p. 190
9.1 Introduction	p. 190
9.2 Anthraquinones and Intercalation into Duplex DNA	p. 190
9.3 Interactions with Higher-Order DNA	p. 192
9.4 Telomerase and Cancer	p. 192
9.5 First-Generation G-Quadruplex Ligands	p. 193
9.6 Molecular Models for Quadruplex-Trisubstituted Acridine Complexes	p. 197
9.7 Cellular and Pharmacological Properties of Trisubstituted Acridines	p. 200
9.8 Conclusions	p. 201
Acknowledgements	p. 202
References	p. 202
Chapter 10 The Mechanism of Action of Telomestatin, a G-Quadruplex-Interactive Compound	p. 207
10.1 Introduction	p. 207
10.1.1 Telomere Structure in Mammals and Telomerase	p. 207
10.1.2 Mechanism of Inhibition of Telomerase by Telomestatin	p. 211
10.1.3 The Stoichiometry of Binding of Telomestatin to the Human Telomeric G-Quadruplex	p. 212
10.1.4 Identity of the Telomeric G-Quadruplex Formed in the Presence of Telomestatin	p. 214
10.1.5 Proposed Models for Telomestatin Binding to the Human Telomeric G-Quadruplex Structure	p. 215
10.1.6 Potential Effect of Telomestatin on the Assembly of Telomeres into Higher-Order Structures	p. 224
10.1.7 Genomic Instability Caused by Telomestatin Treatment and Activation of DNA Damage Response	p. 226
10.1.8 Other Mechanisms of Telomestatin in Mediating its Biological Activity	p. 226
10.2 Concluding Remarks	p. 228
Acknowledgments	p. 228
References	p. 228
Chapter 11 Structural Features of the Specific Interactions between Nucleic Acids and Small Organic Molecules	p. 233
11.1 Introduction	p. 233
11.2 Diels-Alder Ribozymes	p. 234
11.3 Theophylline and Flavin Mononucleotide Binding	p. 238
11.4 Purine Riboswitches	p. 240
11.5 Adenosine Monophosphate Binding	p. 245
11.6 Conclusions	p. 247
11.7 Perspectives	p. 248
References	p. 249
Subject Index	p. 253

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