Natural Products in Medicinal Chemistry

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.

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

• 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 2012IntroductionThe Sponge-Derived Nucleoside Link to DrugsInitial Recognition of Microbial Secondary Metabolites as Antibacterial DrugsBeta-Lactams of All ClassesTetracycline DerivativesGlycopeptide AntibacterialsLipopeptide AntibacterialsMacrolide AntibioticsPleuromutilin DerivativesPrivileged StructuresThe Origin of the BenzodiazepinesBenzopyrans: A Source of Unusual Antibacterial and Other AgentsMultiple Enzymatic Inhibitors from Relatively Simple Natural Product Secondary MetabolitesA Variation on BIOS: The "Inside-Out" ApproachOther Privileged StructuresPrivileged Structures and Inhibitors of Protein-Protein InteractionsUnderprivileged ScaffoldsSo Where Should One Look in the Twenty-First Century for Novel Structures from Natural Sources?Conclusions NATURAL PRODUCT-DERIVED AND NATURAL PRODUCT-INSPIRED COMPOUND COLLECTIONSIntroductionModern Approaches to Produce Natural Product LibrariesPrefractionated Natural Product LibrariesLibraries of Pure Natural ProductsSemisynthetic Libraries of Natural Product-Derived CompoundsSynthetic LIbraries of Natural Product-Inspired CompoundsCompound Collections with Carbocyclic Core StructuresCompound Cllections iwth Oxa-Heterocyclic ScaffoldsCompound Collections with Aza-Heterocyclic ScaffoldsMacrocyclic Compound CollectionsOutlook PART TWO: From Marketed Drugs to Designed Analogs and Clinical Candidates CHEMISTRY AND BIOLOGY OF EPOTHILONESIntroduction: Discovery and Biological ActivitySynthesis of Natural EpothilonesSynthesis and Biological Activity of Nonnatural EpothilonesConformational Studies and Pharmacophore ModelingConclusions TAXOL, TAXOIDS, AND RELATED TAXANESIntroduction and Historical BackgroundMechanism of Action and Drug ResistanceStructure-Activity Relationships (SAR) of TaxolStructural and Chemical Biology of TaxolNew-Generation Taxoids from 10-DABTaxoids in Clinical DevelopmentNew Applications of TaxanesConclusions and Perspectives CAMPTOTHECIN AND ANALOGSIntroductionBiology ActivityCamptothecin in Clinical Use and Under Clinical TrialsChemistryStructure-Activity RelationshipXenograft StudiesProdrug/TargetingDevelopments of Modern Chromatographic Methods Applied to CPTConclusions and Perspectives A SHORT HISTORY OF THE DISCOVERY AND DEVELOPMENT OF NALTREXONE AND OTHER MORPHINE DERIVATIVESIntroductionHistory and DevelopmentPharmacologyStructure-Activity Relationship of Morphine and its AnalogsConclusions and Outlook LINCOSAMIDE ANTIBACTERIALSIntroductionMechanism of ActionAntibacterial SpectrumResistancePseudomembraneous ColitisNext-Generation LincosamidesConclusions PLATENSIMYCIN AND PLATENCINIntroduction and Historical BackgroundDiscovery and Bioactivities of Platensimycin and PlatencinTotal and Formal Syntheses of Platensimycin Total and Formal Syntheses of PlatencinAnalogs of Platensimycin and PlatencinConclusions and Perspective FROM NATURAL PRODUCT TO NEW DIABETES THERAPY: PHLORIZIN AND THE DISCOVERY OF SGLT2 INHIBITOR CLINICAL CANDIDATESIntroductionPhlorizin: A Drug Lead from Apple TreesPhlorizin: Mechanism of ActionPhlorizin, SGLTs, and DiabetesPhlorizin Analogs: O-GlucosidesPhlorizin Analogs: C-GlucosidesC-Glucosides: Aglycone ModificationsC-Glucosides: Sugar ModificationsConclusions AERUGINOSINS AS THROMBIN INHIBITORSIntroductionTargeting the Blood Coagulation CascadeStructure of ThrombinThe Aeruginosin FamilyMimicking NatureConclusions PART THREE: Natural Products as an Incentive for Enabling Technologies MACROLIDES AND ANTIFUNGALS VIA BIOTRANSFORMATIONIntroduction to Polyketides and Their ActivityMechanism of Polyketide BiosynthesisConclusions UNNATURAL NUCLEOSIDE ANALOGS FOR ANTISENSE THERAPYNature Uses Nucleid Acid Polymers for Storage, Transfer, Synthesis, and Regulation of Genetic InformationThe Antisense Approach to Drug DiscoveryThe Medicinal Chemistry Approach to Oligonucleotide DrugsStructural Features of DNA and RNA DuplexesImproving Binding Affinity of Oligonucleotides by Structural Mimicry of RNAImproving Binding Affinity of Oligonucleotides by Conformational Restraint of DNA -The Bicyclo- and Tricyclo-DNA Class of Nucleid Acid AnalogsImproving Binding Affinity of Oligonucleotides by Conformational Restraint of the Phosphodiester Backbone -Alpha, Beta-Constrained Nucleic AcidsNaturally Occurring Backbone ModificationsNaturally Occurring Heterocycle ModificationsOutlook HYBRID NATURAL PRODUCTSIntroductionStaurosporines (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 BRYOLOGSIntroductionIntroduction to Function-Oriented SynthesisIntroduction to BryostatinBryostatin Total SynthesesApplication of FOS to the Bryostatin ScaffoldConclusions CYCLOPAMINE AND CONGENERSIntroductionThe Discovery of CyclopamineAccessibility of CyclopamineThe Hedgehog Signaling PathwayMedical Relevance of Cyclopamine and the Hedgehog Signaling PathwayFurther Modulators of the Hedgehog Signaling PathwaySummary 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 RETROSPECTIVEIntroductionStructure-Based Organic SynthesisNucleosidesBeta-LactamsMorphinomimeticsHistone Deacetylase InhibitorsPactamycin AnalogsAeruginosins: From Natural Products to Achiral AnalogsAvermectin B1a and Bafilomycin A1Bafilomycin A13-N,N-Dimethylamino LincomycinOxazolidinone Ketolide MimeticsEpilogue