Details

Natural Products in Medicinal Chemistry

Methods & Principles in Medicinal Chemistry, Band 60 1. Aufl.

von: Stephen Hanessian, Raimund Mannhold, Hugo Kubinyi, Gerd Folkers
162,99 €
Verlag:	Wiley-VCH
Format:	PDF
Veröffentl.:	18.12.2013
ISBN/EAN:	9783527676552
Sprache:	englisch
Anzahl Seiten:	652

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Beschreibungen

Titelbeschreibung

The inspiration provided by biologically active natural products to conceive of hybrids, congeners, analogs and unnatural variants is discussed by experts in the field in 16 highly informative chapters. Using well-documented studies over the past decade, this timely monograph demonstrates the current importance and future potential of natural products as starting points for the development of new drugs with improved properties over their progenitors. The examples are chosen so as to represent a wide range of natural products with therapeutic relevance among others, as anticancer agents, antimicrobials, antifungals, antisense nucleosides, antidiabetics, and analgesics. From the content: * Part I: Natural Products as Sources of Potential Drugs and Systematic Compound Collections * Part II: From Marketed Drugs to Designed Analogs and Clinical Candidates * Part III: Natural Products as an Incentive for Enabling Technologies * Part IV: Natural Products as Pharmacological Tools * Part V: Nature: The Provider, the Enticer, and the Healer

Inhaltsverzeichnis

Preface PART ONE: Natural Products as Sources of Potential Drugs and Systematic Compound Collections NATURAL PRODUCTS AS DRUGS AND LEADS: AN INTRODUCTION AND PERSPECTIVE AS OF THE END OF 2012 Introduction The Sponge-Derived Nucleoside Link to Drugs Initial Recognition of Microbial Secondary Metabolites as Antibacterial Drugs Beta-Lactams of All Classes Tetracycline Derivatives Glycopeptide Antibacterials Lipopeptide Antibacterials Macrolide Antibiotics Pleuromutilin Derivatives Privileged Structures The Origin of the Benzodiazepines Benzopyrans: A Source of Unusual Antibacterial and Other Agents Multiple Enzymatic Inhibitors from Relatively Simple Natural Product Secondary Metabolites A Variation on BIOS: The "Inside-Out" Approach Other Privileged Structures Privileged Structures and Inhibitors of Protein-Protein Interactions Underprivileged Scaffolds So Where Should One Look in the Twenty-First Century for Novel Structures from Natural Sources? Conclusions NATURAL PRODUCT-DERIVED AND NATURAL PRODUCT-INSPIRED COMPOUND COLLECTIONS Introduction Modern Approaches to Produce Natural Product Libraries Prefractionated Natural Product Libraries Libraries of Pure Natural Products Semisynthetic Libraries of Natural Product-Derived Compounds Synthetic LIbraries of Natural Product-Inspired Compounds Compound Collections with Carbocyclic Core Structures Compound Cllections iwth Oxa-Heterocyclic Scaffolds Compound Collections with Aza-Heterocyclic Scaffolds Macrocyclic Compound Collections Outlook PART TWO: From Marketed Drugs to Designed Analogs and Clinical Candidates CHEMISTRY AND BIOLOGY OF EPOTHILONES Introduction: Discovery and Biological Activity Synthesis of Natural Epothilones Synthesis and Biological Activity of Nonnatural Epothilones Conformational Studies and Pharmacophore Modeling Conclusions TAXOL, TAXOIDS, AND RELATED TAXANES Introduction and Historical Background Mechanism of Action and Drug Resistance Structure-Activity Relationships (SAR) of Taxol Structural and Chemical Biology of Taxol New-Generation Taxoids from 10-DAB Taxoids in Clinical Development New Applications of Taxanes Conclusions and Perspectives CAMPTOTHECIN AND ANALOGS Introduction Biology Activity Camptothecin in Clinical Use and Under Clinical Trials Chemistry Structure-Activity Relationship Xenograft Studies Prodrug/Targeting Developments of Modern Chromatographic Methods Applied to CPT Conclusions and Perspectives A SHORT HISTORY OF THE DISCOVERY AND DEVELOPMENT OF NALTREXONE AND OTHER MORPHINE DERIVATIVES Introduction History and Development Pharmacology Structure-Activity Relationship of Morphine and its Analogs Conclusions and Outlook LINCOSAMIDE ANTIBACTERIALS Introduction Mechanism of Action Antibacterial Spectrum Resistance Pseudomembraneous Colitis Next-Generation Lincosamides Conclusions PLATENSIMYCIN AND PLATENCIN Introduction and Historical Background Discovery and Bioactivities of Platensimycin and Platencin Total and Formal Syntheses of Platensimycin Total and Formal Syntheses of Platencin Analogs of Platensimycin and Platencin Conclusions and Perspective FROM NATURAL PRODUCT TO NEW DIABETES THERAPY: PHLORIZIN AND THE DISCOVERY OF SGLT2 INHIBITOR CLINICAL CANDIDATES Introduction Phlorizin: A Drug Lead from Apple Trees Phlorizin: Mechanism of Action Phlorizin, SGLTs, and Diabetes Phlorizin Analogs: O-Glucosides Phlorizin Analogs: C-Glucosides C-Glucosides: Aglycone Modifications C-Glucosides: Sugar Modifications Conclusions AERUGINOSINS AS THROMBIN INHIBITORS Introduction Targeting the Blood Coagulation Cascade Structure of Thrombin The Aeruginosin Family Mimicking Nature Conclusions PART THREE: Natural Products as an Incentive for Enabling Technologies MACROLIDES AND ANTIFUNGALS VIA BIOTRANSFORMATION Introduction to Polyketides and Their Activity Mechanism of Polyketide Biosynthesis Conclusions UNNATURAL NUCLEOSIDE ANALOGS FOR ANTISENSE THERAPY Nature Uses Nucleid Acid Polymers for Storage, Transfer, Synthesis, and Regulation of Genetic Information The Antisense Approach to Drug Discovery The Medicinal Chemistry Approach to Oligonucleotide Drugs Structural Features of DNA and RNA Duplexes Improving Binding Affinity of Oligonucleotides by Structural Mimicry of RNA Improving Binding Affinity of Oligonucleotides by Conformational Restraint of DNA - The Bicyclo- and Tricyclo-DNA Class of Nucleid Acid Analogs Improving Binding Affinity of Oligonucleotides by Conformational Restraint of the Phosphodiester Backbone - Alpha, Beta-Constrained Nucleic Acids Naturally Occurring Backbone Modifications Naturally Occurring Heterocycle Modifications Outlook HYBRID NATURAL PRODUCTS Introduction Staurosporines (Amino Acid-Sugar Hybrids) Lincomycins (Amino Acid-Sugar Hybrids) Madindolines (Amino Acid-Polyketide Hybrids) Kainoids (Amino Acid-Terpene Hybrids) Benanomicin-Pradimicin Antibiotics (Sugar-Polyketide Hybrids) Angucyclines (Sugar-Polyketide Hybrids) Furaquinocins (Polyketide-Terpene Hybrids) Conclusions PART FOUR: Natural Products as Pharmacological Tools RETHINKING THE ROLE OF NATURAL PRODUCTS: FUNCTION-ORIENTED SYNTHESIS, BRYOSTATIN, AND BRYOLOGS Introduction Introduction to Function-Oriented Synthesis Introduction to Bryostatin Bryostatin Total Syntheses Application of FOS to the Bryostatin Scaffold Conclusions CYCLOPAMINE AND CONGENERS Introduction The Discovery of Cyclopamine Accessibility of Cyclopamine The Hedgehog Signaling Pathway Medical Relevance of Cyclopamine and the Hedgehog Signaling Pathway Further Modulators of the Hedgehog Signaling Pathway Summary and Outlook PART FIVE: Nature: The Provider, the Enticer, and the Healer HYBRIDS, CONGENERS, MIMICS, AND CONSTRAINED VARIANTS SPANNING 30 YEARS OF NATURAL PRODUCTS CHEMISTRY: A PERSONAL RETROSPECTIVE Introduction Structure-Based Organic Synthesis Nucleosides Beta-Lactams Morphinomimetics Histone Deacetylase Inhibitors Pactamycin Analogs Aeruginosins: From Natural Products to Achiral Analogs Avermectin B1a and Bafilomycin A1 Bafilomycin A1 3-N,N-Dimethylamino Lincomycin Oxazolidinone Ketolide Mimetics Epilogue

Rezension

“Generally, it is a well-presented book and can be used as a useful reference by natural products researchers.” (ChemMedChem, 1 November 2014)

Autorenportrait

Stephen Hanessian holds the Isis Pharmaceuticals Research Chair at the University of Montreal and is also on the faculty of the Departments of Chemistry, Pharmaceutical Sciences and Pharmacology at the University of California, Irvine. He has received numerous awards and distinctions, the latest being the 2012 Ernest Guenther Award in the Chemistry of Natural Products from the American Chemical Society, the IUPAC-Richter Prize in Medicinal Chemistry, and the Montreal InVivo Prize for innovation. Professor Hanessian has over 500 journal publications to his name, which span a wide cross-section of areas related to organic, bioorganic, and medicinal chemistry. His latest book "Design and Strategy in Organic Synthesis - From the Chiron Approach to Catalysis" (Wiley-VCH) has received wide acclaim.