Advances In Dna Sequence Specific Agents

This series encompasses design, synthesis, application, and analytical methods (including clinical and in vitro) for the study of these critical interactions. As our understanding of the genome and proteome expands, general developments in the field of DNA sequence specific interaction are likely to play an increasingly important role. Accordingly, manuscripts have been solicited from experts covering a diverse range of fields, reflecting the cross-disciplinary and dynamic nature of the series. Volume 4 describes work on the modification of DNA by AT specific anticancer drugs, DNA alkylation events which involve metabolite generation, DNA sequence recognition by two selective binders, bulged DNA microenvironments as molecular targets, DNA sequence specific binding by short peptides and the analysis of DNA-protein interactions using DNase I footprinting methodology. Features include: • Expert contributors from the Biomedical world • Emerging areas of drug design and therapeutic applications • Nucleic acid-protein interactions • Color graphics of molecular modeling analyses • New and emerging methodologies

In this volume the entire focus is devoted to the macromolecule target specificity of DNA interactive developmental therapeutic agents of current interest. A brief introduction to DNA interactive anticancer agents is included for readers who may benefit from an overview surrounding the developments that have contributed to our general understanding of this field. The following nine chapters have been carefully chosen so that they describe topics which are at the forefront of development in DNA-targeted cancer chemotherapy. Issues that have been addressed include the mechanisms of selective DNA topoisomerase I and II poisoning by antitumor agents (Chapters 1 and 2), sequence-specific recognition of DNA by groove-binding drugs and drug-conjugates (Chapters 3 and 4), recent developments in nitrogen mustard alkylating agents and their potential use for antibody-directed enzyme-prodrug therapy (Chapter 5), nonclassical platinum anticancer complexes, including dinuclear and trans-platinum derivatives (Chapter 6), DNA cleaving antitumor chromoproteins containing reactive enediyne moieties, which exhibit interesting free-radical chemistry along with selective targeting (Chapter 7), the potential of new sequence-specific antisense and antigene therapy in oncology (Chapter 8), and finally the conceivable chemotherapeutic use of mimetics of the DNA structure, obtained by substitution of the sugar-phosphate natural chain with a peptide backbone, the so-called peptide nucleic acids (Chapter 9). Important approaches being currently investigated for selective cancer treatment, such as gene therapy and immunochemotherapy, are not discussed in this volume since they fall beyond its scope.

In this volume the entire focus is devoted to the macromolecule target specificity of DNA interactive developmental therapeutic agents of current interest. A brief introduction to DNA interactive anticancer agents is included for readers who may benefit from an overview surrounding the developments that have contributed to our general understanding of this field. The following nine chapters have been carefully chosen so that they describe topics which are at the forefront of development in DNA-targeted cancer chemotherapy. Issues that have been addressed include the mechanisms of selective DNA topoisomerase I and II poisoning by antitumor agents (Chapters 1 and 2), sequence-specific recognition of DNA by groove-binding drugs and drug-conjugates (Chapters 3 and 4), recent developments in nitrogen mustard alkylating agents and their potential use for antibody-directed enzyme-prodrug therapy (Chapter 5), nonclassical platinum anticancer complexes, including dinuclear and trans-platinum derivatives (Chapter 6), DNA cleaving antitumor chromoproteins containing reactive enediyne moieties, which exhibit interesting free-radical chemistry along with selective targeting (Chapter 7), the potential of new sequence-specific antisense and antigene therapy in oncology (Chapter 8), and finally the conceivable chemotherapeutic use of mimetics of the DNA structure, obtained by substitution of the sugar-phosphate natural chain with a peptide backbone, the so-called peptide nucleic acids (Chapter 9). Important approaches being currently investigated for selective cancer treatment, such as gene therapy and immunochemotherapy, are not discussed in this volume since they fall beyond its scope.

DNA sequence specificity is a sub-specialty in the general area of molecular recognition. This area includes macromolecular-molecular interactions (e.g., protein-DNA), oligomer-DNA interacitons (e.g., triple strands), and ligand-DNA interactions (e.g., drug-DNA). It is this latter group of DNA sequence specificity interactions that is the subject of Volumes 1 and 2 of Advances in DNA Sequence Specific Agents. As was the case for Volume 1, Part A also covers methodology, but in Volume 2 we include calorimetric titrations, molecular modeling, X-ray crystallographic and NMR structural studies, and transcriptional assays. Part B also follows the same format as Volume 1 and describes the sequence specificities and covalent and noncovalent interactions of small ligands with DNA. This volume is aimed in general at scientists who have an interest in deciphering the molecular mechanisms for sequence recognition of DNA. The methods have general applicability to small molecules as well as oligomers and proteins, while the examples provide general principles involved in sequence recognition.

In this volume the entire focus is devoted to the macromolecule target specificity of DNA interactive developmental therapeutic agents of current interest. A brief introduction to DNA interactive anticancer agents is included for readers who may benefit from an overview surrounding the developments that have contributed to our general understanding of this field. The following nine chapters have been carefully chosen so that they describe topics which are at the forefront of development in DNA-targeted cancer chemotherapy. Issues that have been addressed include the mechanisms of selective DNA topoisomerase I and II poisoning by antitumor agents (Chapters 1 and 2), sequence-specific recognition of DNA by groove-binding drugs and drug-conjugates (Chapters 3 and 4), recent developments in nitrogen mustard alkylating agents and their potential use for antibody-directed enzyme-prodrug therapy (Chapter 5), nonclassical platinum anticancer complexes, including dinuclear and trans-platinum derivatives (Chapter 6), DNA cleaving antitumor chromoproteins containing reactive enediyne moieties, which exhibit interesting free-radical chemistry along with selective targeting (Chapter 7), the potential of new sequence-specific antisense and antigene therapy in oncology (Chapter 8), and finally the conceivable chemotherapeutic use of mimetics of the DNA structure, obtained by substitution of the sugar-phosphate natural chain with a peptide backbone, the so-called peptide nucleic acids (Chapter 9). Important approaches being currently investigated for selective cancer treatment, such as gene therapy and immunochemotherapy, are not discussed in this volume since they fall beyond its scope.

DNA sequence specificity is a sub-specialty in the general area of molecular recognition. This area includes macromolecular-molecular interactions (e.g., protein-DNA), oligomer-DNA interacitons (e.g., triple strands), and ligand-DNA interactions (e.g., drug-DNA). It is this latter group of DNA sequence specificity interactions that is the subject of Volumes 1 and 2 of Advances in DNA Sequence Specific Agents. As was the case for Volume 1, Part A also covers methodology, but in Volume 2 we include calorimetric titrations, molecular modeling, X-ray crystallographic and NMR structural studies, and transcriptional assays. Part B also follows the same format as Volume 1 and describes the sequence specificities and covalent and noncovalent interactions of small ligands with DNA. This volume is aimed in general at scientists who have an interest in deciphering the molecular mechanisms for sequence recognition of DNA. The methods have general applicability to small molecules as well as oligomers and proteins, while the examples provide general principles involved in sequence recognition.

The binding of antibiotics and drugs to DNA is a fast developing area of research with important applications in medicine, particularly the treatment of cancer. Sequence-specific DNA Binding Agents uniquely discusses key aspects of this topic, providing a novel perspective on the subject. Written by experts in the field, this book discusses diverse modes of binding of antibiotics and drugs to DNA, emphasising matters that are important or promising for cancer treatment. Chapters discuss established agents like actinomycin D but also look at novel drugs with strong potential in chemotherapy such as new topoisomerase inhibitors, telomerase inhibitors, peptide nucleic acids and triple helix-forming oligonucleotides. There are also sections discussing methodological advances including computational methods, slow kinetics, melting curve analysis and approaches to medicinal chemistry. Finally there is a section on RNA structure and its potential as a drug target. The book is ideal for researchers in industry and academia who require a comprehensive source of reference to this rapidly expanding subject.

There have been remarkable advances towards discovering agents that exhibit selectivity and sequence-specificity for DNA, as well as understanding the interactions that underlie its propensity to bind molecules. This progress has important applications in many areas of biotechnology and medicine, notably in cancer treatment as well as in future gene targeting therapies. The editor and contributing authors are leaders in their fields and provide useful perspectives from diverse and interdisciplinary backgrounds on the current status of this broad area. The role played by chemistry is a unifying theme. Early chapters cover methodologies to evaluate DNA-interactive agents and then the book provides examples of DNA-interactive molecules and technologies in development as therapeutic agents. DNA-binding metal complexes, peptide and polyamide–DNA interactions, and gene targeting tools are some of the most compelling topics treated in depth. This book will be a valuable resource for postgraduate students and researchers in chemical biology, biochemistry, structural biology and medicinal fields. It will also be of interest to supramolecular chemists and biophysicists.