Contents

Preface

Chapter 1

Human Topoisomerase I and Its Inhibitors: Recent Developments

Abstract

1.1. Introduction

1.2. TopoIA

1.3. TopoIB

1.4. TopoIC

1.5. Crystal Structure and Domain Properties

1.6. TopoI Inhibitors

1.7. Classification of TopoI Inhibitors

1.7.1. Camptothecin Derivatives

1.7.2. Non-Camptothecin Derivatives

a. Indolocarbazoles

b. Quinazolinocarbolines

c. Pyranopyrrolo Isoquinoline

d. Pyrroloiminoquinones

e. Anthraquinone Derivatives

f. Phenanthrene/Azaphenanthrenes

g. Arylisoquinoline Derivatives

h. Polyphenols

i. Chromen Derivatives

j. Azacridine Derivatives

k. Miscellaneous Agents

References

Chapter 2

Pharmacoinformatics Studies on Human Topoisomerase II: Exploring the Mechanism of Enzyme Inhibition

Abstract

2.1. Introduction

2.2. Pharmacoinformatics Methods in Drug Design

2.2.1. Homology Modeling

2.2.2. Molecular Docking

2.2.3. Molecular Dynamics Simulations

2.2.4. Quantitative Structure-Activity Relationship

2.2.5. Virtual Screening

2.3. Human Topoisomerase II

2.3.1. Structural Organization of hTopoII

2.3.2. Various Events in the Catalytic Cycle of hTopoII

2.3.3. Base Preferences at the Cleavage Site in DNA

2.3.4. Types of hTopoII Inactivation

2.3.4.1. The hTopoII Poisons Inhibit the DNA-Resealing Step

2.3.4.2. The hTopoII Catalytic Inhibitors Prevent the DNA-Cleavage

2.3.5. Isoform Specificity of Anti-hTopoII Agents

2.4. Molecular Modeling Studies on hTopoII

2.4.1. Exploring the Molecular Recognition Interactions of Inhibitors with hTopoII

2.4.1.1. ATP-Binding Site

2.4.1.2. ICRF-Binding Site

2.4.1.3. Merbarone-Binding Site

2.4.1.4. Etoposide-Binding Site

2.4.1.5. Intercalator-Binding Site

2.4.2. Understanding the Molecular Basis of Isoform Specificity

2.4.3. Correlating the Structure and Activity of Inhibitors

2.5. Conclusion

Acknowledgments

References

Chapter 3

Targeting Human Topoisomerase-II: Opportunities in Cancer Chemotherapy

Abstract

3.1. Topoisomerases

3.1.1. Classification of Topoisomerases

3.1.2. Topoisomerase I (TopoI)

Structure and Mechanism of hTopoI

3.1.3. Topoisomerase II

Structure and Mechanism of hTopoIIα

3.2. Topoisomerase Inhibitors as Anticancer Agents

3.2.1. hTopoI Inhibitors as Anticancer Agents

3.2.2. hTopoII Inhibitors as Anticancer Agents

a) hTopoII Poisons

DNA Intercalating hTopoII Poisons

Anthracyclines

Amino-Acridine

Anthracenedione

Ellipticine

DNA Non-Intercalating hTopoII Poisons

b) hTopoII Catalytic Inhibitors

Interfering the Binding between DNA and hTopoII

Aclarubicin

Suramin

ATP-Competitive Inhibitor

Stabilize Noncovalent DNA- hTopoII Complexes

Traping hTopoII in Close Clamp

3.2.3. Problems Associated with hTopoII Inhibiting Drugs

Acknowledgment

References

Chapter 4

Adverse Effects of Topoisomerase Inhibitors: Limits the Dosage for Anticancer Therapy

Abstract

4.1 Introduction

4.1. Types of Topoisomerase Inhibitors and Their Adverse Effects

4.1.1. Camptothecin

4.1.2. Topotecan

4.1.3. Irinotecan

4.1.4. Epipodophyllotoxins

4.1.5. Etoposide

4.1.6. Teniposide

4.1.7. Semi-Synthetic Anthracyclines

Mitoxantrone

4.1.8. Adjuvant Therapy

4.1.9. Anthracyclines

Therapeutic and Preventive Strategies:

4.2. Mechanisms of Toxicities Shown by Topoisomerase Inhibitors

4.2.1. Gastrointestinal Toxicity

4.2.2. Cardiotoxicity

A. Doxorubicin-Induced Oxidative Stress

i. Mitochondrial Reactive Oxygen Species (ROS)

ii. Nitric Oxide Synthase-Dependent ROS

iii. Nicotinamide Adenine Dinucleotide Phosphate NAD(P)H Dependent ROS

iv. Fe-Doxorubicin Complex

B. Apoptosis

C. Intracellular Calcium Dysregulation

4.2.3. Myelosuppression

4.2.4. Hypersensitivity Reactions (HSRs)

4.3. Side Effects Associated with Topoisomerase Inhibition: Approaches to Overcome

References

Chapter 5

Topoisomerases Genetics and Its Associated Diseases

Abstract

5.1. Introduction

5.2. Disorders Associated with Topoisomerases

5.3. Topoisomerases Binding Proteins and Tumorigenesis

5.4. Genetic Variations in Topoisomerases and Its Pharmacogenetics

5.5. Drug Interactions and Topoisomerases SNPS

5.6 Conclusion

References

Chapter 6

Interaction between Topoisomerases and Histone Deacetylases: Role in Cancer Progression and Therapeutic Interventions

Abstract

6.1. Introduction

6.2. Impact of Topoisomerases and HDACs in Cancer Progression, Problem Associated with Monotherapy

6.3. Evidence Supporting Interaction between Topoisomerases and HDACs

References

Editor Contact Information

Index

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