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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 i...

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Bibliographic Details
Main Author:	Wilman, D.E.
Format:	eBook
Language:	English
Published:	Dordrecht Springer Netherlands 1990, 1990
Edition:	1st ed. 1990
Subjects:	Inorganic Chemistry Chemistry, Organic Oncology Organic Chemistry
Online Access:	https://doi.org/10.1007/978-94-009-0397-5?nosfx=y
Collection:	Springer Book Archives -2004 - Collection details see MPG.ReNa

Table of Contents:

12.2.2 Reaction chemistry and mechanism of action
12.3 Carboplatin
12.3.1 Synthesis and characterisation
12.3.2 Reaction chemistry and mechanism of action
12.4 Iproplatin 336 12.4.1 Synthesis and characterisation
12.4.1 Synthesis and characterisation
12.4.2 Reaction chemistry and mechanism of action
12.5 Compounds containing the 1,2-diaminocyclohexane ligand
12.6 Concluding remarks
References
13 Hypoxia-selective agents: radiosensitisers and cytotoxins
13.1Introduction
13.2 Radiosensitisers
13.2.1 Nitroxyl free radicals
13.2.2 Electron-affinic radiosensitisers
13.3 Hypoxia-mediated cytotoxins
13.4 Concluding remarks
References
14 The chemistry and structure-activity relationships of some new prodrugs of vinca alkaloids
14.1 Introduction
14.2 History
14.3 Structure-activity relationships
14.4 Chemical modifications
14.4.1 Nomenclature and abbreviations
14.4.2 C-23 terminal modification
14.4.3 C-4 modification
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
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 Synthesis of alkylmelamines
11.5.2 Synthesis of N-hydroxymethylmelamines
11.5.3 Radiolabeled syntheses
11.5.4 Crystal structure
11.6 Concluding remarks
References
12 The chemistry of platinum antitumour agents
12.1 Introduction
12.2 Cisplatin
12.2.1 Synthesis and characterisation
17.8 Partial synthesis of 7-substituted chromophoric analogues
17.9 Tetracyclic chromophoric analogues
17.10 Summary
References
18 Ellipticines
18.1 Isolation and structure of the pyrido[4,3-6]carbazole alkaloids
18.2 Synthesis
18.2.1 Syntheses involving the formation of ring B
18.2.2 Syntheses requiring the formation of ring C as the last step information of the tetracycle
18.2.3 Syntheses utilising ring D formation as the last step in construction of the tetracycle
18.3 Structure-activity studies
18.4 Theories of the mode of action
18.4.1 Intercalation and the effect on topoisomerases
18.4.2 Alkylation of macro-biomolecules
18.4.3 Radical and superoxide formation
18.5 Clinical applications
18.6 Subjective comments
References
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
14.5 Discussion
References
15 The chemistry of mitomycins
15.1 Introduction
15.2 Mitomycins and acids
15.3 Mitomycins and base
15.4 Mitomycin rearrangements
15.5 Chemistry at C-7
15.6 Mitomycins-metal complexes
15.7 Chemistry in the reduced state
15.7.1 Bioreductive alkylation as the mode of action of the mitomycins
15.7.2 Bioreductive alkylation products with DNA
References
16 The chemistry of activated bleomycin
16.1 Introduction
16.2 Activation of metallobleomycins
16.3 Chemistry of DNA strand scission
16.4 Bleomycin-mediated degradation of structurally altered DNA substrates
References
17 Actinomycins
17.1 Introduction
17.2 Mode of action
17.3 Natural structural variations
17.4 Biosynthetic analogues
17.5 Total synthesis of peptidic analogues
17.6 Total synthesis of chromophoric analogues
17.7 Partial synthesis of 2-substituted chromophoric analogues
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
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
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)

The Chemistry of Antitumour Agents

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