Antineoplastic Drugs Organic Syntheses

Dr Daniel Lednicer's career in both the private and public sectors has been devoted to the search for new therapeutic agents. He spent two decades at the bench as a chemist at the Upjohn Company. Following that, he served as director of chemical research at Mead Johnson, director of pharmaceutical sciences at Adria Laboratories, and pharmaceutical manager at Analytical Biochemistry Laboratories. Most recently, he was a project officer at the National Cancer Institute. Dr Lednicer is the acclaimed author of several books on drug synthesis and discovery, including 7 volumes of the series Organic Chemistry of Drug Synthesis (Wiley US).

Preface ix

Introduction xi

1 Alkylating Agents 1

1.1 bis-Chloroethyl Amines 1

1.2 Several Other Chloroethyl Agents 5

1.3 Platinum-Based Antineoplastic Agents 6

1.4 Miscellaneous Alkylating Agents 8

2 Antimetabolites 13

2.1 Introduction 13

2.2 Folate Antagonists 14

2.3 Pyrimidines and Purines 21

3 Hormone Blocking Anticancer Drugs 31

3.1 Introduction 31

3.2 Estrogen Antagonists 32

3.3 Androgen Antagonists 44

4 Topoisomerase Inhibitors 55

4.1 Introduction 55

4.2 Anthracyclines 56

4.3 Anthraquinones and Anthrapyrazoles 59

4.4 Camptothecins 65

4.5 Miscellaneous Topoisomerase Inhibitors 74

5 Mitotic Inhibitors 81

5.1 Introduction 81

5.2 Taxanes 82

5.3 Wholly Synthetic Compounds 86

6 Matrix Metalloproteinase Inhibitors 97

6.1 Introduction 97

6.2 Hydroxamates 98

7 Histone Deacetylase Inhibitors 109

7.1 Introduction 109

7.2 Hydroxamates 110

7.3 Phenylenediamines 113

8 Enzyme Inhibitor, Part I, Tyrosine Kinases 117

8.1 Introduction 117

8.2 Epidermal Growth Factor Inhibitors 118

8.3 VEGF 124

8.4 SRC Nonreceptor Tyrosine Kinase 134

8.5 PDGF 138

8.6 EGF 141

8.7 Other TKI 143

8.8 Janus Kinase Inhibitors 154

9 Enzyme Inhibitors: Part II Additional Targets 161

9.1 Serine–Threonine Kinase Inhibitors 161

9.2 Additional Enzyme Inhibitors 166

10 Miscellaneous Antineoplastic Agents 187

10.1 Acyclic 187

10.2 Monocyclic 188

10.3 Two Linked Rings 190

10.4 Rings on a Chain 191

10.5 Fused Rings 195

Appendix A 203

Combinatorial Chemistry 203

Index of Heterocyclic Sytheses 205

Subject Index 207

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