Medicinal Chemistry of Anticancer Drugs

List of Figures

List of Tables

Preface

Abbreviations

Chapter 1. Introduction

1. SOME GENERAL REMARKS ABOUT CANCER AND CANCER CHEMOTHERAPY

2. A BRIEF ACCOUNT OF THE ROLE OF CHEMISTRY IN CANCER CHEMOTHERAPY

3. NATURAL PRODUCTS IN CANCER CHEMOTHERAPY

4. A BRIEF COMMENT ABOUT CANCER NANOTECHNOLOGY

5. CONCLUSION

Chapter 2. Antimetabolites

1. INTRODUCTION

2. INHIBITORS OF THE BIOSYNTHESIS OF URIDYLIC ACID

3. INHIBITORS OF THE BIOSYNTHESIS OF 2′-DEOXYRIBONUCLEOTIDES BY RIBONUCLEOTIDE REDUCTASE (RNR)

3.1. Structure and catalytic cycle of RNR

3.2. Radical scavengers as inhibitors of RNR

3.3. Substrate analogs as RNR inhibitors

3.4. Allosteric inhibition of RNR

4. INHIBITORS OF THE BIOSYNTHESIS OF THYMIDILIC ACID

4.1. Thymidylate synthase

4.2. 5-fluorouracil (5-FU) and floxuridine

4.3. 5-FU prodrugs

4.4. Modulation of 5-FU activity

4.5. Folate-Based TS inhibitors

5. INHIBITORS OF DIHYDROFOLATE REDUCTASE (DHFR)

5.1. Classical DHFR inhibitors

5.2. Nonclassical (lipophilic) DHFR inhibitors

6. INHIBITORS OF THE DE NOVO PURINE BIOSYNTHESIS PATHWAY

6.1. Inhibitors of phosphoribosylpyrophosphate (PRPP) amidotransferase

6.2. Inhibitors of glycinamide ribonucleotide formyltransferase (GARFT)

6.3. Inhibitors of phosphoribosylformylglycinamidine synthetase

6.4. Inhibitors of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase

6.5. Thiopurines and related compounds

7. INHIBITORS OF ADENOSINE DEAMINASE

8. INHIBITORS OF LATE STAGES IN DNA SYNTHESIS

8.1. Pyrimidine nucleosides

8.2. Purine nucleosides

9. ANTIMETABOLITE ENZYMES

Chapter 3. Anticancer Drugs That Inhibit Hormone Action

1. INTRODUCTION

2. ESTROGENS AND THEIR INVOLVEMENT IN CARCINOGENESIS

3. ANTIESTROGENS AS ANTITUMOR DRUGS

3.1. Nonsteroidal antiestrogens (SERMs)

3.2. Steroidal antiestrogens

4. AROMATASE INHIBITORS

4.1. Aromatase mechanism of action

4.2. Steroidal aromatase inhibitors (type I inhibitors)

4.3. Nonsteroidal aromatase inhibitors (type II)

5. STEROID SULFATASE INHIBITORS

6. ANDROGEN-RELATED ANTITUMOR AGENTS

6.1. Antiandrogens

6.2. Inhibitors of 14α-demethylase and 17α-hydroxylase

6.3. Inhibitors of 5α-reductase

7. REGULATION OF STEROIDAL HORMONE SYNTHESIS AS A TARGET FOR ANTITUMOR DRUGS

7.1. Introduction

7.2. GnRH (LHRH) agonists

7.3. GnRH (LHRH) antagonists

8. MISCELLANEOUS STEROID HORMONE-RELATED ANTICANCER THERAPY

8.1. Gestagens as antitumor agents

8.2. Glucocorticoids and inhibitors of their biosynthesis as antitumor agents

9. COMPOUNDS ACTING ON OTHER PROTEINS OF THE NUCLEAR RECEPTOR SUPERFAMILY: RETINOIDS

REFERENCES

Chapter 4. Anticancer Drugs Acting via Radical Species, Photosensitizers and Photodynamic Therapy of Cancer

1. INTRODUCTION: RADICALS AND OTHER REACTIVE OXYGEN SPECIES

2. BIOLOGICAL EFFECTS OF ROS

2.1. Membrane phospholipid peroxidation

2.2. Malondialdehyde generation and its consequences

2.3. DNA strand cleavage

2.4. Oxidation of DNA bases

2.5. Formaldehyde generation

2.6. ROS as signaling molecules

3. ANTHRACYCLINES AND THEIR ANALOGS

4. MITOXANTRONE AND RELATED QUINONES

5. ACTINOMYCIN D

6. CHARTREUSIN, ELSAMICIN A, AND RELATED COMPOUNDS

7. BLEOMYCINS

8. ENEDIYNE ANTIBIOTICS

9. TIRAPAZAMINE

10. PENCLOMEDINE

11. RADIOSENSITIZERS

12. PHOTODYNAMIC THERAPY OF CANCER

Chapter 5. DNA Alkylating Agents

1. INTRODUCTION

2. NITROGEN MUSTARDS

2.1. Introduction

2.2. DNA alkylation by nitrogen mustards and cytotoxicity mechanisms

2.3. Structure–activity relationships in nitrogen mustards

2.4. Site-directed nitrogen mustards

3. AZIRIDINES (ETHYLENEIMINES)

4. EPOXIDES

5. METHANESULFONATES

6. NITROSOUREAS

7. TRIAZENES

8. METHYLHYDRAZINES

9. 1,3,5-TRIAZINES: HEXAMETHYLMELAMINE AND TRIMELAMOL

10. PLATINUM COMPLEXES

11. MISCELLANEOUS ALKYLATING AND ACYLATING ANTITUMOR AGENTS

Chapter 6. Alkylating and Non-Alkylating Compounds Interacting with the DNA Minor Groove

1. INTRODUCTION

2. NETROPSIN, DISTAMYCIN, AND RELATED COMPOUNDS

3. MITOMYCINS

4. TETRAHYDROISOQUINOLINE ALKALOIDS

5. CYCLOPROPYLINDOLE ALKYLATING AGENTS

6. PYRROLO[1,4]BENZODIAZEPINES

Chapter 7. DNA Intercalators and Topoisomerase Inhibitors

1. DNA INTERCALATION AND ITS CONSEQUENCES

2. MONOFUNCTIONAL INTERCALATING AGENTS

2.1. Ellipticine and its analogues

2.2. Actinomycins

2.3. Fused quinoline compounds

2.4. Naphthalimides and related compounds

2.5. Chartreusin, elsamicin A, and related compounds

2.6. Other monofunctional intercalating agents

3. BIFUNCTIONAL INTERCALATING AGENTS

4. DNA TOPOISOMERASES

4.1. Topoisomerase I mechanism

4.2. Topoisomerase II mechanism

5. TOPOISOMERASE II POISONS

5.1. Acridine derivatives

5.2. Anthracyclines and related compounds

5.3. Non-intercalating topoisomerase II poisons

6. TOPOISOMERASE II CATALYTIC INHIBITORS

6.1. Inhibitors of the binding of topoisomerase II to DNA: Aclarubicin

6.2. Merbarone

6.3. Bis(dioxopiperazines)

7. SPECIFIC TOPOISOMERASE I INHIBITORS

7.1. Camptothecins

7.2. Non-CPT topoisomerase I inhibitors

Chapter 8. Anticancer Drugs Targeting Tubulin and Microtubules

1. INTRODUCTION

2. DRUGS THAT INHIBIT MICROTUBULE POLYMERIZATION AT HIGH CONCENTRATIONS

2.1. Compounds binding at the Vinca site

2.2. Compounds binding at the colchicine site

3. MICROTUBULE-STABILIZING AGENTS: COMPOUNDS Binding at the Taxane Site

3.1. Taxanes

3.2. Epothilones

3.3. Miscellaneous marine compounds that bind to the taxane site

4. MISCELLANEOUS ANTICANCER DRUGS ACTING ON NOVEL SITES ON TUBULINE

5. ANTIVASCULAR EFFECTS OF MICROTUBULE-TARGETED AGENTS

6. MITOTIC KINESIN INHIBITORS

Chapter 9. Drugs That Inhibit Signalling Pathways for Tumor Cell Growth and Proliferation

1. INTRODUCTION: THE ROLE OF PROTEIN KINASES IN CANCER

2. SIGNALLING PATHWAYS RELATED TO KINASES

3. INHIBITORS OF TYROSINE KINASES (TKs)

3.1. Inhibitors of EGFRs (HER-1)

3.2. Inhibitors of other receptors of the EGFR family: HER-2

3.3. Inhibitors of insulin-like growth factor receptors: IGFR-1

3.4. Inhibitors of TKs with pro-angiogenic activity: VEFGR and related kinases

3.5. Inhibitors of FLT-3

3.6. Inhibitors of BCR-ABL TK (Abelson kinase)

3.7. Dual Inhibitors of BCR-ABL and Src TKs

4. INHIBITORS OF SERINE-THREONINE KINASES

4.1. Cyclin-Dependent Kinases

4.2. PDK1, AKT, and mTOR kinases

4.3. Aurora kinases

4.4. PKC modulators

5. INHIBITORS OF THE RAS–RAF–MEK SIGNALLING PATHWAY AND FARNESYL TRANSFERASE

5.1. Inhibitors of Ras protein expression

5.2. Inhibitors of Ras processing by farnesyltranferase

5.3. Inhibitors of downstream effectors of Ras function

6. INHIBITORS OF FARNESYLDIPHOSPHATE SYNTHASE AND GERANYLGERANYLDIPHOSPHATE SYNTHASE

7. ANTICANCER DRUGS ACTING ON APOPTOTIC SIGNALLING PATHWAYS

7.1. BCL-2 proteins

7.2. p53 proteins

7.3. Death receptors

7.4. Nuclear factor κB

8. INHIBITORS OF HEAT-SHOCK PROTEINS (HSP 90)

Chapter 10. Other Approaches to Targeted Therapy

1. PROTEASOME INHIBITORS

2. ANTIANGIOGENIC AGENTS UNRELATED TO KINASE SIGNALING

2.1. Inhibitors of proteolytic enzymes of the extracellular matrix: Metalloproteinases

2.2. Inhibitors of other targets related to the extracellular matrix: Heparanase

2.3. Endogenous inhibitors of angiogenesis

2.4. Inhibitors of cellular adhesion molecules

2.5. Miscellaneous antiangiogenic compounds

3. EPIGENETIC THERAPY OF CANCER

3.1. Inhibitors of DNA methyltransferases (DNMT)

3.2. Inhibitors of histone deacetylases (HDAC)

3.3. Regulators of histone methylation

4. INHIBITORS OF OTHER DNA-ASSOCIATED ENZYMES

4.1. Telomerase inhibitors

4.2. DNA repair system inhibitors

5. THERAPY DIRECTED AT OTHER TARGETS

5.1. Antisense oligonucleotides

5.2. Monoclonal antibodies against cancer cells

5.3. Gene therapy

5.4. Antitumor agents targeted at lysosomes

Chapter 11. Drug Targeting in Anticancer Chemotherapy

1. INTRODUCTION

2. PRODRUG-BASED ANTICANCER DRUG TARGETING: SMALL-MOLECULE PRODRUGS

2.1. Selective enzyme expression in tumor cells

2.2. Hypoxia-based strategies for tumor-specific prodrug activation

2.3. Gene-directed enzyme prodrug therapy (GDEPT) and virus-directed enzyme prodrug therapy (VDEPT)

2.4. Antibody-directed enzyme prodrug therapy (ADEPT)

3. POLYMER-PROTEIN CONJUGATES

4. MACROMOLECULAR SMALL-DRUG CARRIER SYSTEMS

4.1. N-(2-Hydroxypropyl)methacrylamide polymers

4.2. Poly-(l-glutamic)conjugates

4.3. Neuropeptide Y conjugates

4.4. PEGylated conjugates

4.5. Immunoconjugated drugs

5. POLYMER-DIRECTED ENZYME PRODRUG THERAPY (PDEPT)

6. FOLATE RECEPTOR-TARGETED CHEMOTHERAPY AND IMMUNOTHERAPY OF CANCER

7. LIPOSOMES AND NANOPARTICLES IN ANTICANCER DRUG TARGETING

7.1. Liposomes

7.2. Nanoparticle albumin bound technology

Chapter 12. Drugs That Modulate Resistance to Antitumor Agents

1. ATP-Binding Cassette Efflux Pumps in Anticancer Drug Resistance

1.1. General features of ABC efflux pumps

1.2. P-glycoprotein

2. Glutathione and Glutathione-S-Transferase in Anticancer Drug Resistance

2.1. Inhibitors of glutathione biosynthesis

2.2. Inhibitors of glutathione-S-transferase

3. Chemosensitizers Targeting DNA-Repair Systems

3.1. Inhibitors of O6-alkylguanine-DNA alkyltransferase

3.2. Potential antitumor adjuvants targeting the BER process

3.3. Inhibitors of enzymes involved in double-strand DNA break repair pathways

4. Antitumor Drug Resistance Related to Extracellular pH: Tumor-Associated Carbonic Anhydrase as an Anticancer Target

Chapter 13. Cancer Chemoprevention

1. INTRODUCTION

2. LIGANDS FOR NUCLEAR RECEPTORS IN CANCER CHEMOPREVENTION

3. ANTI-INFLAMMATORY AGENTS AND ANTIOXIDANTS IN CANCER CHEMOPREVENTION

3.1. COX-2 inhibitors and other anti-inflammatory agents

3.2. Antioxidants

4. CHROMATIN MODIFIERS IN CANCER CHEMOPREVENTION

5. MISCELLANEOUS AGENTS FOR CHEMOPREVENTION

6. CANCER VACCINES

Index