Natural Products in Medicinal Chemistry

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 welldocumented 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

InhaltsangabePreface 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 SpongeDerived Nucleoside Link to Drugs Initial Recognition of Microbial Secondary Metabolites as Antibacterial Drugs BetaLactams 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 StructureActivity Relationships (SAR) of Taxol Structural and Chemical Biology of Taxol NewGeneration Taxoids from 10DAB 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 StructureActivity 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 StructureActivity Relationship of Morphine and its Analogs Conclusions and Outlook LINCOSAMIDE ANTIBACTERIALS Introduction Mechanism of Action Antibacterial Spectrum Resistance Pseudomembraneous Colitis NextGeneration 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 CGlucosides: Aglycone Modifications CGlucosides: 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 NUCLE

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