Inhibitors of Nucleic Acid Synthesis

During the last decade physical and chemical methods have improved rapidly - a fact which allowed the mode of action of antibiotics to be studied - and many biochemically-oriented scientists have devoted their research to the following questions: 1. What is the metabolic pathway that is inhibited selectively, and what are the target molecules within a sensitive cell? 2. What are the relationships between the chemical structure of an antibiotic and the physicochemical properties of the sensitive mole­ cule(s)? 3. Why and how far is the action selective? 4. Is it possible to correlate the interaction with the target mole­ cule(s) with the particular biological activities observed? This monograph deals with those antibiotics which interfere with the biosynthesis of nucleic acids. The idea was to provide an insight into how to investigate the preceding questions experimentally and to solve as yet unresolved problems rather than to give a review of the current state of knowledge. Although the biochemistry of nucleic acid synthesis is known in general, the precise molecular mechanisms by which deoxyribonucleic acid is replicated or transcribed has still to be clarified. For this reason it is not yet possible to describe the molecular mechanisms by which the inhibitors of nucleic acid and protein synthesis exhibit their effects. The fact that the inhibitors of nucleic acid and protein synthesis themselves served as useful tools to obtain an insight into the mechanisms of replication, transcription and translation was one of the most exciting discoveries in this field.

Contenu

General Introduction.- I. Inhibitors of DNA Synthesis.- A. Mitomycin.- 1. Origin, Biological and Chemical Properties.- 2. On the Molecular Mechanism of Action.- a) Interaction with DNA in Vitro.- b) Interaction with DNA within the Cell.- c) Effect on DNA Metabolism.- d) Effect on RNA Metabolism.- 3. Particular Activities in Biological Systems.- a) Synthesis of Enzymes.- b) Mutagenicity.- c) Chromosome Breakage.- d) Viruses, Phages and Episomal DNA.- e) Mitosis.- f) Immune Response.- B. Streptonigrin.- 1. Origin, Biological and Chemical Properties.- 2. On the Molecular Mechanism of Action.- 3. Particular Activities in Biological Systems.- C. Sibiromycin.- D. Phleomycin.- 1. Origin, Biological and Chemical Properties.- 2. On the Molecular Mechanism of Action.- a) Interaction of Phleomycin with Nucleic Acids in Vitro.- b) Effect on DNA- and RNA-Dependent Processes in Vitro.- c) Effects on Nucleic Acids and Their Metabolism in Normal and Virus-Infected Cells.- d) Particular Activities in Biological Systems.- E. Bleomycin.- 1. Origin, Biological and Chemical Properties.- 2. On the Molecular Mechanism of Action.- a) Interaction with DNA in Vitro.- b) Effect on DNA-Dependent Processes in Vitro.- c) Effects on Nucleic Acids and Their Metabolism within the Cell.- F. Neocarcinostatin.- 1. Origin, Biological and Chemical Properties.- 2. On the Mechanism of Action.- G. Edeine.- H. Nalidixic Acid.- 1. Origin, Biological and Chemical Properties.- 2. Mechanism of Action and Biological Activities.- a) Effect on DNA and Nucleic Acid Metabolism.- b) Mutagenicity.- c) Recombination.- d) Hemolysin Production.- II. Inhibitors of RNA Synthesis that Interact with the DNA Template.- A. Actinomycin.- 1. Origin, Biological and Chemical Properties.- 2. On the Molecular Mechanism of Action.- a) Interaction with DNA, Poly- and Mononucleotides in Vitro.- b) Interaction with Deoxyguanosine.- c) Proposed Models for the Actinomycin-DNA Complex..- d) Inhibition of DNA Dependent RNA Synthesis in Vitro.- e) Effect on RNA Metabolism.- 3. Particular Activities in Biological Systems.- a) Synthesis of Enzymes.- b) Phages and Viruses.- c) Immune Response.- B. Anthracyclines.- 1. Origin, Biological and Chemical Properties.- 2. On the Molecular Mechanism of Action.- a) Interaction with DNA in Vitro.- b) Interaction of Planar Dyes with DNA and tRNA in Vitro.- c) Effect on DNA-Dependent Processes in Vitro.- d) Effect on Nucleic Acid Metabolism.- 3. Particular Activities in Biological Systems.- a) Viruses and Phages.- b) Mutagenicity of Intercalating Dyes.- c) Chemotherapeutic Aspects.- C. Chromomycin, Olivomycin and Mithramycin.- 1. Origin, Biological and Chemical Properties.- 2. On the Molecular Mechanism of Action.- a) Interaction with DNA in Vitro.- b) Effects on DNA-Dependent Processes in Vitro.- c) Effects on Nucleic Acid Metabolism.- 3. Particular Activities against Viruses.- D. Kanchanomycin.- 1. Origin, Biological and Chemical Properties.- 2. On the Mechanism of Action.- E. Distamycin and Netropsin.- 1. Origin, Biological and Chemical Properties.- 2. On the Molecular Mechanism of Action.- a) Interaction with DNA in Vitro.- b) Effect on DNA-Dependent Processes in Vitro.- F. Anthramycin.- 1. Origin, Biological and Chemical Properties.- 2. On the Molecular Mechanism of Action.- a) Interaction with DNA in Vitro.- b) Inhibition of DNA-Dependent Processes in Vitro and within the Cell.- c) Chemosterilant Action of Anthramycin.- III. Inhibitors of RNA Synthesis Interacting with RNA Polymerases.- A. Rifamycins.- 1. Origin, Biological and Chemical Properties.- 2. On the Molecular Mechanism of Action.- a) Interaction with RNA Polymerase in Vitro.- b) On the Mechanism of Inhibition of RNA Polymerase Reaction.- c) Effect on RNA in Intact Cells or Organelles.- 3. Particular Activities in Biological Systems.- a) Bacteriophages, Viruses and Episomes.- b) Trachoma Agent.- B. Streptovaricin.- 1. Origin, Biological and Chemical Properties.- 2. On the Molecular Mechanism of Action.- C. Streptolydigin.- 1. Origin, Biological and Chemical Properties.- 2. On the Molecular Mechanism of Action.- D. Amanitins.- 1. Origin, Biological and Chemical Properties.- 2. On the Molecular Mechanism of Action.- a) Interaction of Amanitins with Eukaryotic RNA Polymerases.- b) Effects on RNA Metabolism.- IV. Inhibitors Interferring at the Precursor Level or with Regulatory Processes of Nucleic Acid Synthesis.- A. Nucleoside Antibiotics.- a) Toyocamycin, Tubercidin, Sangivamycin.- b) Cordycepin.- c) 3 '-Amino-3 '-Deoxyadenosine.- d) Formycin.- e) 6 (p-Hydroxyphenylazo)-Uracil (HPUra).- B. Mycophenolic Acid.- C. Amino Acid Analogs.- a) Azaserine and DON.- b) Azotomycin.- c) Hadacidin.- D. Quinone Antibiotics 1.- Granaticin, Mitomycin Derivatives, Synthetic Quinones.- 1. Origin, Biological and Chemical Properties.- 2. Mechanism of Action.- References.