Doxorubicin

Doxorubicin: Anticancer Antibiotics details the development of doxorubicin as a wide-spectrum antitumor antibiotic. The book begins by tracing the discovery and development of doxorubicin, highlighting factors such as (a) the involvement of organic chemistry at an early stage, which allowed the rapid identification of doxorubicin and ensured its prompt availability for the clinical trials; (b) the well-established, pioneering expertise in experimental chemotherapy of Professor Aurelio di Marco and his group at Istituto Nazionale Tumori, Milan; and (c) the highly motivated interest of experienced clinicians.
The remaining chapters provide an overview of basic studies in the area of medicinal chemistry and related fields that have resulted from doxorubicin development. Such studies have been concerned with both biochemical and biophysical investigations at the molecular level and at different levels of biological organization. A large body of work aimed at developing synthetic procedures for the drug and for new related analogs of potential clinical usefulness has also been carried out.

Contenu

Preface
Acknowledgments
1 Discovery and Development of Doxorubicin
Antitumor Activity of an Anthracycline Pigment
Anthracyclines and Anthracyclinones: The First Decade
Daunorubicin
The Isolation of Doxorubicin
The Structure and Stereochemistry of Doxorubicin
Antitumor Activity on Experimental Tumors
Clinical Activity of Doxorubicin
Analytical Development and Synthesis of Radiolabeled Doxorubicin
Conjugates and Complexes of Doxorubicin as Antitumor Agents
References
2 Total Synthesis of Doxorubicin and Related Compounds
Wong's Synthesis of Daunomycinone
Other Syntheses Starting from 3-Methoxyphthalate and a Tetralin or Their Equivalents
Closure of Ring A in Substituted Anthraquinones and Their Derivatives
Applications of the Diels - Alder Reaction for the Construction of Ring A
Other Syntheses Based on Diels-Alder Condensation
Syntheses Based on Different Principles
The Carbohydrate Moiety
Other Studies Related to Ring A Functionalization
References
3 Molecular Interactions
X-Ray Diffraction Studies
Association and Dissociation Equilibria in Solution
Oxidoreduction Behavior
Complexes with Metal Ions
The DNA Intercalation Complex
Protein Binding
Phospholipids
Mucopolysaccharides
Effect of Respiratory Processes in Subcellular Preparations
Interference with Redox Reactions and Formation of Radicals
Inhibition of (Na+ + K+) ATPase and of Ion Transport in Subcellular Preparations
References
4 Studies with Living Systems
Uptake and Distribution in Cultured Sensitive Cells
Effects of DNA-Related Cell Functions in Vitro
Other Studies in Cultured Cells
Studies with Resistant Cells
Studies with Cultured Heart Cells
Metabolism
Pharmacokinetics
Pharmacological Properties in Whole Mammalian Systems
References
5 Analogues Modified in Ring A Substitution
Derivatization at C-13 and C-14
Side-Chain Oxidative Degradation
Modifications at C-9 and C-10
Substitution at C-8
4-Demethoxy-7,10-Ethanodaunomycinone
References
6 Analogues Modified in the Aminosugar Residue
The L-Arabino Analogues and the Development of 4'-Epidoxorubicin
Other Analogues Modified at C-4'
Other Configurational Analogues
Other Functional Analogues
Disaccharides
Amides
N,N-Dimethyldaunorubicin
Nonsugar Derivatives
References
7 Analogues Modified in the Anthraquinone Chromophore
Synthesis of 4-Demethoxydaunorubicins
Properties of 4-Demethoxydaunorubicins
Other Synthetic Approaches to 4-Demethoxy Analogues
New Ring D-Substituted 4-Demethoxydaunorubicins and 4-Demethoxydoxorubicins
Replacement of 4-O-Methyl and Other Alkyl Groups
The 6-O-Methyl and 11-O-Methyl Derivatives
5-Iminodaunorubicin
Recent Developments
References
8 New Developments in Biosynthetic Anthracyclines
The Rhodomycins and Related Compounds
Pyrromycinone and Aklavinone Glycosides
Biosynthetic Glycosides Related to Daunorubicin
Other Anthracycline Antibiotics
The Biosynthesis of the Anthracyclines
Microbial Transformations
References
Index