The Chemistry of Antitumour Agents

Walter C. J. ROSS Emeritus Professor, University of London To paraphrase a statement made by Howard E. Skipper many years ago, 'We cancer chemotherapists have often exploited and overworked our chemist colleagues and they have been conveniently forgotten at award giving times'. This book is an attempt to rectify this and highlight the contribution of the chemist in modifying the structure of various types of agent to enhance their effectiveness as inhibitors of the growth of neoplastic tissues. Cancer chemotherapy is a relatively new discipline, coming later than the introduction of sulphonamides and antibiotics. Modern anti-cancer therapy started with the report of the use of a war gas methyl-di-(2-chloroethyl)amine (HN2) in 1946 for the treatment of Hodgkin's disease. The recognition that this compound acted as a bifunctional alkylating agent under physiological conditions led to the synthesis of a wide range of drugs with similar properties. Amongst these were chlorambucil, melphalan, busulphan, and cyclophos phamide which still find use today. Somewhat later, a range of antibiotics was found to be effective, for example aminopterin (1948) and 6-mercaptopurine (1958) to treat acute leukaemias and 5-fluorouracil and 6-azauracil (1957-8) which were used against a variety of cancers. Since these early days the net has been cast ever wider and, as well as ingenious modifications of the compounds mentioned above, anticancer drugs now include growing classes of compounds ranging from purely synthetic agents to natural products. Many of these are discussed in the present book.

Inhalt
1 Acridine-based antitumour agents.- 1.1 Introduction.- 1.2 Nitracrine (NSC 247561) and analogues.- 1.2.1 Synthesis.- 1.2.2 Properties.- 1.3 Amsacrine (NSC 249992) and analogues.- 1.3.1 Synthesis.- 1.3.2 Properties.- 1.4 CI-921 (NSC 343499) and other amsacrine analogues.- 1.4.1 Synthesis.- 1.4.2 Properties.- 1.5 N, N'-Bis-(9-acridinyl)-1,6-hexanediamine (NSC 219733) and related di- and triacridines.- 1.5.1 Synthesis.- 1.5.2 Properties.- 1.5.3 Triacridines.- 1.6 N-[2-(Dimethylamino)ethyl] -9-aminoacridine-4-carboxamide (NSC 342965) and related acridinecarboxamides.- 1.6.1 Synthesis.- 1.6.2 Properties.- 1.7 Conclusions.- References.- 2 Antitumour anthracyclines.- 2.1 Introduction and historical development.- 2.2 Doxorubicin.- 2.2.1 Microbiological isolation.- 2.2.2 Chemical preparation.- 2.2.3 Analytical profile.- 2.3 Epirubicine (4'-epidoxorubicin).- 2.3.1 Preparation.- 2.3.2 Analytical profile.- 2.4 Idarubicine (4-demethoxydaunorubicin).- 2.4.1 Preparation.- 2.4.2 Analytical profile.- 2.5 Spectroscopic properties.- 2.5.1 Infrared spectra.- 2.5.2 Mass spectra.- 2.5.3 Nuclear magnetic resonance spectra.- 2.5.4 Ultraviolet and visible spectra.- 2.5.5 Fluorescence spectra.- 2.5.6 Circular dichroism.- 2.6 Stability and reactivity.- 2.7 Metabolism.- 2.7.1 Synthesis of C-14 14C-labelled derivatives.- 2.7.2 Metabolism in patients.- 2.8 Methods of analysis.- 2.8.1 Spectroscopic analysis.- 2.8.2 Thin-layer chromatography.- 2.8.3 Liquid chromatography.- 2.8.4 Determination of anthracyclines in biological fluids.- 2.9 Aclacinomycin A.- 2.9.1 Microbiological isolation.- 2.9.2 Analytical profile.- 2.9.3 Spectroscopic properties.- 2.9.4 Metabolism.- References and notes.- 3 Alkylating agents.- 3.1 Introduction.- 3.2 Classification of biological alkylating agents.- 3.3 Reactivityof alkylating species.- 3.3.1 The reaction mechanisms of the alkylating agents with water and other nucleophiles.- 3.3.2 The electrophilicity of alkylating agents.- 3.3.3 Formation of DNA adducts.- 3.3.4 Structural modulation of alkylating agent reactivity.- 3.4 Chemical features involved in the transport and uptake of alkylating agents.- 3.4.1 Lipophilicity.- 3.4.2 Molecular structure.- 3.5 Preparative chemistry.- 3.5.1 Sulphur mustards.- 3.5.2 Nitrogen mustards.- 3.5.3 Aziridines.- 3.5.4 Methanesulphonates.- 3.5.5 Oxiranes.- 3.5.6 Benzo- and naphthoquinones.- 3.5.7 Piperazinediones.- 3.5.8 Diazoalkanes.- 3.5.9 ?-Methylene-?-lactones.- 3.5.10 Alkyl halides.- 3.6 The metabolism of alkylating agents.- 3.6.1 Cyclophosphamide and iphosphamide metabolism.- 3.6.2 Metabolism of CB 1954.- 3.7 Quantitative structure-activity relationships of the alkylating agents.- 3.7.1 Optimisation of lipophilicity by QSAR analysis.- 3.7.2 Separation of the structural features responsible for adverse effects from those responsible for activity.- 3.7.3 Structural effects in the carrier molecules.- 3.8 Concluding remarks.- References.- 4 Nitrosoureas.- 4.1 Introduction.- 4.2 Structure-activity relationships.- 4.2.1 Leukaemia L 1210.- 4.2.2 Solid tumours.- 4.3 Toxicity.- 4.4 Chemical basis of biologic activity.- 4.5 Structure and latentiation.- 4.5.1 Enzymic activation.- 4.5.2 Chemical activation.- 4.6 Structure and stability.- 4.7 Structure and metabolism.- 4.8 Water-soluble nitrosoureas and chlorozotocin analogues.- 4.9 Structural modifications and special carrier groups: aspirations.- References.- 5 Triazenes.- 5.1 Introduction.- 5.2 1-Aryl- and 1-heteryl-3, 3-dialkyltriazenes.- 5.2.1 Synthesis and structure.- 5.2.2 Antitumour activity.- 5.2.3 Metabolism.- 5.2.4 Chemistry.- 5.33-Alkyl-1-aryltriazenes.- 5.3.1 Synthesis.- 5.3.2 Structure.- 5.3.3 Chemistry.- 5.3.4 Monoalkyltriazenes as heterocyclic synthons.- 5.3.5 Biochemistry.- 5.4 Hydroxymethyltriazenes.- 5.5 Bis-triazenes: N, N-bis-(1-aryl-3-methyltriazen-3-ylmethyl)methylamines.- 5.6 1,3-Dialkyl- and 1,3,3-trialkyltriazenes.- 5.6.1 Synthesis.- 5.6.2 Reactions.- 5.6.3 Biological activity.- 5.7 Triazene N-oxides.- 5.8 Concluding remarks.- References.- 6 The chemistry of azolotetrazinones.- 6.1 Introduction.- 6.2 Synthesis.- 6.3 Reactions involving opening of the tetrazinone ring.- 6.4 Reactions involving retention of the tetrazinone ring.- 6.5 Relationship of the chemistry of the azolotetrazinones to their biochemistry.- 6.6 Concluding remarks.- References.- 7 Chemistry of antifolates.- 7.1 Introduction.- 7.2 Inhibitors of dihydrofolate reductase (EC 1.5.1.3).- 7.3 Inhibitors of thymidylate synthase (EC 2.1.1.45).- 7.4 Inhibitors of purine biosynthesis.- 7.5 The polyglutamyl metabolites of antifolates.- 7.6 Concluding remarks.- References.- 8 Inhibitors of steroid hormone biosynthesis and action.- 8.1 Introduction.- 8.2 Drugs for the treatment of breast cancer.- 8.2.1 Aminoglutethimide.- 8.2.2 4-Hydroxyandrost-4-ene-3,17-dione.- 8.2.3 Danazol.- 8.2.4 Tamoxifen.- 8.2.5 Medroxyprogesterone acetate.- 8.3 Drugs for the treatment of prostatic cancer.- 8.3.1 Luteinising hormone-releasing hormone agonists.- 8.3.2 Ketoconazole.- 8.3.3 4-Azasteroids as 5?-reductase inhibitors.- 8.3.4 Cyproterone acetate.- 8.3.5 Bifluranol.- 8.3.6 Flutamide.- 8.4 Concluding remarks.- References.- 9 Anticancer pyrimidines, pyrimidine nucleosides and prodrugs.- 9.1 Introduction.- 9.2 5-Fluorouracil and related 5-fluoropyrimidine compounds.- 9.2.1 Synthesis of 5-fluorouracil, nucleosides and derivatives.- 9.2.2 Mode ofaction and catabolism of 5-fluorouracil.- 9.3 1-(?-D-Arabinofuranosyl)cytosine.- 9.3.1 Syntheses of 1-(?-D-arabinofuranosyl)cytosine.- 9.4 5-Azacytidine and related nucleosides.- 9.4.1 Syntheses of 5-azacytidine and analogues.- 9.5 Selected experimental agents.- 9.6 Prodrugs of pyrimidines and pyrimidine nucleosides.- 9.6.1 Prodrugs of 1-(?-D-arabinofuranosyl)cytosine.- 9.6.2 Prodrugs of 5-fluorouracil and 2'-deoxy-5-fluorouridine.- 9.6.3 2,2'-Anhydro-l-(?-D-arabinofuranosyl)-5-fluorocytosine.- 9.7 Conclusions.- References.- 10 Purines and purine nucleoside analogues as antitumour agents.- 10.1 Introduction.- 10.2 Purine analogues.- 10.3 Purine nucleosides.- 10.4 Purine cyclic nucleotides.- 10.5 Certain other nucleosides biochemically related to purines.- 10.5.1 Tiazofurin.- 10.5.3 Pyrazofurin.- 10.5.4 2'-Deoxycoformycin (pentostatin).- References.- 11 Methylmelamines.- 11.1 Introduction.- 11.2 Hexamethylmelamine.- 11.3 Pentamethylmelamine.- 11.4 Trimelamol.- 11.5 Chemistry.- 11.5.1 Synthesi…