Sequence-specific DNA Binding Agents

by Waring, Michael

• ISBN13: 9780854043705
• ISBN10: 0854043705
• Edition: 1st
• Format: Hardcover
• Copyright: 2006-11-15
• Publisher: Royal Society of Chemistry

Summary

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.

Table of Contents

DNA Recognition by Triple Helix Formation	p. 1
Introduction	p. 1
Triplets and Triplex Motifs	p. 1
Strategies to Increase Triplex Stability	p. 3
Sugar Modifications	p. 3
Addition of Positive Charges	p. 4
Backbone Modifications	p. 9
Base Stacking	p. 10
Triplex-Binding Ligands	p. 10
Overcoming the pH Dependency	p. 11
Pyrimidine Base Analogues	p. 12
Purine Base Analogues	p. 13
Recognition of Pyrimidine Interruptions	p. 14
Null Bases and Abasic Linkers	p. 14
Natural Bases	p. 15
Nucleotide Analogues for Recognizing Pyrimidine Interruptions	p. 16
Nucleotide Analogues for Recognizing both Partners of the Base Pair	p. 18
Mixed Sequence Recognition	p. 20
Acknowledgements	p. 22
References	p. 22
Interfacial Inhibitors of Human Topoisomerase I	p. 29
Introduction	p. 29
Molecular Mechanism of Action of Drugs that Trap Top1 Cleavage Complexes	p. 33
Intercalation between the Base Pairs Flanking the Top1-Mediated DNA Break	p. 33
DNA Untwisting by Drugs at the Top1-Mediated DNA Cleavage Site	p. 35
Common Hydrogen-Bond Network for Top1 Inhibitors Bound in the Ternary Complex	p. 37
Generalization of the Interfacial Inhibitor Concept	p. 39
Acknowledgments	p. 41
References	p. 41
Diversity of Topoisomerase I Inhibitors for Cancer Chemotherapy	p. 44
Introduction	p. 44
Camptothecins	p. 47
Indenoisoquinolines	p. 51
Benzimidazoles	p. 54
Indolocarbazoles	p. 54
Phenanthridines and Related Compounds	p. 56
Marine Alkaloids	p. 58
Plant Natural Products	p. 59
Conclusion	p. 60
References	p. 60
Slow DNA Binding	p. 69
Introduction - Kinetics vs. Thermodynamics of DNA Binding	p. 69
Different DNA-Binding Modes - Different DNA-Binding Kinetics	p. 71
External Electrostatic Binding	p. 74
Groove Binding	p. 75
Intercalation	p. 76
Threading Intercalation	p. 77
Common Slow DNA Binders	p. 78
Actinomycin D	p. 78
Nogalamycin	p. 80
Ruthenium Complexes Exhibiting Slow DNA Binding Kinetics	p. 82
Bis-intercalating Ru-dimer [[Mu]-c4(cpdppz)[subscript 2] (phen)[subscript 4]Ru[subscript 2][superscript 4]+	p. 84
Semirigid Ru-dimer [[Mu]-11,11[prime]-bidppz)(x)[subscript 4]Ru[subscript 2]+ (x=phen or bipy)	p. 87
References	p. 91
DNA Gene Targeting using Peptide Nucleic Acid (PNA)	p. 96
Introduction	p. 96
Duplex DNA Recognition in vitro	p. 97
PNA Conjugates	p. 99
Effect of PNA Binding on DNA Structure	p. 100
Cellular Gene Targeting	p. 101
Activation of Gene Transcription	p. 102
Gene-Targeted Repair	p. 102
Cellular Delivery and Bioavailability in vivo	p. 102
Prospects	p. 103
References	p. 103
Actinomycin D: Sixty Years of Progress in Characterizing a Sequence-Selective DNA-Binding Agent	p. 109
Summary	p. 109
Introduction	p. 110
Historical Perspectives	p. 110
DNA-Binding Studies: The Early Years	p. 113
The Intercalation Model	p. 113
Sequence-Selectivity of Actinomycin D	p. 115
Characterization of the Actinomycin D-DNA Complex	p. 116
Role of Bases Flanking the Actinomycin D-Binding Site	p. 116
Promiscuity in the Sequence Selectivity of Actinomycin D	p. 118
Global vs. Microscopic Sequence-Recognition	p. 119
The Shuffling Hypothesis Revisited	p. 120
Structural Motifs as Actinomycin D Targets	p. 122
The Era of Single-Strand DNA Binding	p. 122
Conclusions	p. 125
Acknowledgments	p. 126
References	p. 126
Thermal Denaturation of Drug-DNA Complexes: Tools and Tricks	p. Shi
Introduction	p. 130
Thermal Denaturation Tools	p. 131
Analysis of T[subscript m] Shifts in the Presence of Drug	p. 131
Obtaining Binding Enthalpy Values by DSC	p. 133
Modeling Melting Curves by McGhee's Algorithm	p. 136
Case Studies: Bisintercalating Anthracyclines and Echinomycin	p. 137
Summary: Advantages and Pitfalls	p. 142
Thermal Denaturation: New Tricks	p. 143
Melting Mixtures to Assess Sequence- and Structural-Selectivity	p. 143
Advantages and Prospects	p. 148
Summary	p. 148
Acknowledgments	p. 148
References	p. 148
Computer Simulations of Drug-DNA interactions: A Personal Journey	p. 152
Introduction	p. 152
Minor Groove DNA Binders	p. 155
Natural Bifunctional Intercalators and Hoogsteen Base Pairing	p. 158
Bis-Intercalation of Echinomycin and Related Bifunctional Agents in Relation to Binding Sequence Preferences	p. 162
Binding Preferences of Synthetic Pyridocarbazole Bis-Intercalators	p. 167
Sequence Selectivity of Actinomycin D	p. 169
Binding of the Potent Antitumour Agent Trabectedin to DNA	p. 171
Lamellarins as Topoisomerase I Poisons	p. 176
Concluding Remarks	p. 179
Acknowledgements	p. 179
References	p. 179
The Discovery of G-Quadruplex Telomere Targeting Drugs	p. 190
Introduction	p. 190
Anthraquinones and Intercalation into Duplex DNA	p. 190
Interactions with Higher-Order DNA	p. 192
Telomerase and Cancer	p. 192
First-Generation G-Quadruplex Ligands	p. 193
Molecular Models for Quadruplex-Trisubstituted Acridine Complexes	p. 197
Cellular and Pharmacological Properties of Trisubstituted Acridines	p. 200
Conclusions	p. 201
Acknowledgements	p. 202
References	p. 202
The Mechanism of Action of Telomestatin, a G-Quadruplex-Interactive Compound	p. 207
Introduction	p. 207
Telomere Structure in Mammals and Telomerase	p. 207
Mechanism of Inhibition of Telomerase by Telomestatin	p. 211
The Stoichiometry of Binding of Telomestatin to the Human Telomeric G-Quadruplex	p. 212
Identity of the Telomeric G-Quadruplex Formed in the Presence of Telomestatin	p. 214
Proposed Models for Telomestatin Binding to the Human Telomeric G-Quadruplex Structure	p. 215
Potential Effect of Telomestatin on the Assembly of Telomeres into Higher-Order Structures	p. 224
Genomic Instability Caused by Telomestatin Treatment and Activation of DNA Damage Response	p. 226
Other Mechanisms of Telomestatin in Mediating its Biological Activity	p. 226
Concluding Remarks	p. 228
Acknowledgments	p. 228
References	p. 228
Structural Features of the Specific Interactions between Nucleic Acids and Small Organic Molecules	p. 233
Introduction	p. 233
Diels-Alder Ribozymes	p. 234
Theophylline and Flavin Mononucleotide Binding	p. 238
Purine Riboswitches	p. 240
Adenosine Monophosphate Binding	p. 245
Conclusions	p. 247
Perspectives	p. 248
References	p. 249
Subject Index	p. 253
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