Main description:

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

Contents:

List of Contributors XV Preface XIX Personal Foreword XXI Part One Natural Products as Sources of Potential Drugs and Systematic Compound Collections 1 1 Natural Products as Drugs and Leads to Drugs: An Introduction and Perspective as of the End of 2012 3 David J. Newman and Gordon M. Cragg 1.1 Introduction 3 1.2 The Sponge-Derived Nucleoside Link to Drugs 5 1.3 Initial Recognition of Microbial Secondary Metabolites as Antibacterial Drugs 8 1.4 b-Lactams of All Classes 9 1.5 Tetracycline Derivatives 12 1.6 Glycopeptide Antibacterials 13 1.7 Lipopeptide Antibacterials 16 1.8 Macrolide Antibiotics 18 1.9 Pleuromutilin Derivatives 19 1.10 Privileged Structures 21 1.11 The Origin of the Benzodiazepines 21 1.12 Benzopyrans: A Source of Unusual Antibacterial and Other Agents 22 1.13 Multiple Enzymatic Inhibitors from Relatively Simple Natural Product Secondary Metabolites 23 1.14 A Variation on BIOS: The Inside Out Approach 26 1.15 Other Privileged Structures 26 1.16 Privileged Structures as Inhibitors of Protein Protein Interactions 27 1.17 Underprivileged Scaffolds 30 1.18 So Where Should One Look in the Twenty-First Century for Novel Structures from Natural Sources? 31 1.19 Conclusions 33 References 33 2 Natural Product-Derived and Natural Product-Inspired Compound Collections 43 Stefano Rizzo, Vijay Wakchaure, and Herbert Waldmann 2.1 Introduction 43 2.2 Modern Approaches to Produce Natural Product Libraries 44 2.3 Prefractionated Natural Product Libraries 45 2.4 Libraries of Pure Natural Products 46 2.5 Semisynthetic Libraries of Natural Product-Derived Compounds 46 2.6 Synthetic Libraries of Natural Product-Inspired Compounds 47 2.6.1 Solid-Phase Techniques 48 2.6.2 Solution-Phase Techniques 50 2.6.3 Solid-Supported Reagents and Scavengers 55 2.6.4 Tagging Approach 58 2.7 Compound Collections with Carbocyclic Core Structures 60 2.7.1 Illudin-Inspired Compound Collection 60 2.7.2 Lapochol-Inspired Naphthoquinone Collection 61 2.7.3 A Compound Collection with Decalin Core Structure 62 2.8 Compound Collections with Oxa-Heterocyclic Scaffolds 63 2.8.1 Carpanone-Inspired Compound Collection 63 2.8.2 Calanolide-Inspired Compound Collection 64 2.8.3 Benzopyran-Inspired Compound Collection 65 2.9 Compound Collections with Aza-Heterocyclic Scaffolds 66 2.9.1 Solution-Phase Synthesis of (-) Marinopyrrole A and a Corresponding Library 66 2.9.2 Alkaloid/Terpenoid-Inspired Compound Collection 67 2.10 Macrocyclic Compound Collections 68 2.10.1 Macrosphelide A-Inspired Compound Collection 68 2.10.2 Solid-Phase Synthesis of Analogs of Erythromycin A 69 2.10.3 An Aldol-Based Build/Couple/Pair Strategy for the Synthesis of Macrocycles and Medium-Sized Rings 71 2.11 Outlook 72 References 73 Part Two From Marketed Drugs to Designed Analogs and Clinical Candidates 81 3 Chemistry and Biology of Epothilones 83 Karl-Heinz Altmann and Dieter Schinzer 3.1 Introduction: Discovery and Biological Activity 83 3.2 Synthesis of Natural Epothilones 86 3.3 Synthesis and Biological Activity of Non-natural Epothilones 90 3.3.1 Semisynthetic Derivatives 90 3.3.2 Fully Synthetic Analogs 92 3.4 Conformational Studies and Pharmacophore Modeling 114 3.5 Conclusions 115 References 115 4 Taxol, Taxoids, and Related Taxanes 127 Iwao Ojima, Anushree Kamath, and Joshua D. Seitz 4.1 Introduction and Historical Background 127 4.1.1 Discovery of Taxol (Paclitaxel): An Epoch-Making Anticancer Drug from Nature 127 4.1.2 Taxane Family 128 4.1.3 Sources and Methods of Production 129 4.1.4 Clinical Development of Taxol (Taxol1) 131 4.2 Mechanism of Action and Drug Resistance 132 4.2.1 Taxol, Cell Cycle Arrest, and Apoptosis 132 4.2.2 Drug Resistance to Taxol 133 4.3 Structure Activity Relationships (SAR) of Taxol 133 4.3.1 SAR of Taxol 133 4.3.2 Chemical Modifications of Taxol: Taxol Derivatives and Taxoids 134 4.4 Structural and Chemical Biology of Taxol 141 4.4.1 Bioactive Conformation of Taxol 141 4.4.2 Microtubule-Binding Kinetics of Taxol 145 4.5 New-Generation Taxoids from 10-DAB 145 4.5.1 Taxoids from 10-DAB 145 4.5.2 Taxoids from 14b-Hydroxybaccatin III 148 4.5.3 Taxoids from 9-Dihydrobaccatin III 149 4.6 Taxoids in Clinical Development 150 4.6.1 Docetaxel (Taxotere1, RP 56976) 150 4.6.2 Cabazitaxel (Jevtana1, RPR 116258A, XRP6258) 153 4.6.3 Larotaxel (XRP9881, RPR109881) 153 4.6.4 Ortataxel (SB-T-101131, IDN5109, BAY59-8862, ISN 5109) 154 4.6.5 Tesetaxel (DJ-927) 154 4.6.6 Milataxel (MAC-321, TL 139) 155 4.7 New Applications of Taxanes 155 4.7.1 Taxane-Based MDR Reversal Agents 155 4.7.2 Taxanes as Antiangiogenic Agents 156 4.7.3 Taxanes as Antitubercular Agents 157 4.8 Conclusions and Perspective 158 References 159 5 Camptothecin and Analogs 181 Giuseppe Giannini 5.1 Introduction 181 5.2 Biology Activity 185 5.2.1 Camptothecin Acts on Eukaryotic Top 1 187 5.2.2 Drug Resistance and Topoisomerase Mutation 189 5.2.3 Camptothecin: Beyond the Topoisomerase I 190 5.2.4 Off-Label Investigation 190 5.3 Camptothecin in Clinical Use and Under Clinical Trials 190 5.3.1 Homocamptothecin 203 5.4 Chemistry 204 5.4.1 Total Syntheses 205 5.4.2 Syntheses of Some Representative Camptothecin Derivatives 207 5.5 Structure Activity Relationship 210 5.6 Xenograft Studies 211 5.7 Prodrug/Targeting 212 5.8 Developments of Modern Chromatographic Methods Applied to CPT 214 5.9 Conclusions and Perspectives 214 References 215 6 A Short History of the Discovery and Development of Naltrexone and Other Morphine Derivatives 225 Vimal Varghese and Tomas Hudlicky 6.1 Introduction 225 6.2 History and Development 226 6.3 Pharmacology 238 6.4 Structure Activity Relationship of Morphine and its Analogs 240 6.5 Conclusions and Outlook 244 References 244 7 Lincosamide Antibacterials 251 Hardwin O Dowd, Alice L. Erwin, and Jason G. Lewis 7.1 Introduction 251 7.2 Mechanism of Action 253 7.3 Antibacterial Spectrum 254 7.4 Resistance 257 7.5 Pseudomembranous Colitis 258 7.6 Next-Generation Lincosamides 259 7.7 Conclusions 264 References 264 8 Platensimycin and Platencin 271 Arun K. Ghosh and Kai Xi 8.1 Introduction and Historical Background 271 8.2 Discovery and Bioactivities of Platensimycin and Platencin 272 8.3 Total and Formal Syntheses of Platensimycin 278 8.4 Total and Formal Syntheses of Platencin 283 8.5 Analogs of Platensimycin and Platencin 287 8.6 Conclusions and Perspective 295 References 296 9 From Natural Product to New Diabetes Therapy: Phlorizin and the Discovery of SGLT2 Inhibitor Clinical Candidates 301 Vincent Mascitti and Ralph P. Robinson 9.1 Introduction 301 9.2 Phlorizin: A Drug Lead from Apple Trees 302 9.3 Phlorizin: Mechanism of Action 304 9.4 Phlorizin, SGLTs, and Diabetes 306 9.5 Phlorizin Analogs: O-Glucosides 306 9.6 Phlorizin Analogs: C-Glucosides 309 9.7 C-Glucosides: Aglycone Modifications 314 9.8 C-Glucosides: Sugar Modifications 316 9.9 Conclusions 325 References 325 10 Aeruginosins as Thrombin Inhibitors 333 Juan R. Del Valle, Eric Therrien, and Stephen Hanessian 10.1 Introduction 333 10.2 Targeting the Blood Coagulation Cascade 333 10.3 Structure of Thrombin 335 10.4 The Aeruginosin Family 336 10.4.1 Aeruginosin 298A and Related Microcystis sp. Peptides 336 10.4.2 Oscillarin and Related Oscillatoria sp. Peptides 339 10.4.3 Dysinosin A and Related Peptides from Dysidaedae Sponges 340 10.4.4 Structurally Related Antithrombin Peptide Natural Products 342 10.4.5 Close Analogs of Antithrombotic Aeruginosins 344 10.5 Mimicking Nature 346 10.5.1 The 50-Year Challenge 348 10.5.2 Peptide Analogs 350 10.5.3 Peptidomimetics 352 10.6 Conclusions 355 References 356 Part Three Natural Products as an Incentive for Enabling Technologies 365 11 Macrolides and Antifungals via Biotransformation 367 Aaron E. May and Chaitan Khosla 11.1 Introduction to Polyketides and Their Activity 367 11.2 Mechanism of Polyketide Biosynthesis 367 11.2.1 Erythromycin 371 11.2.2 Avermectin/Doramectin 377 11.2.3 Tetracyclines 381 11.2.4 Salinosporamides 385 11.3 Conclusions 391 References 392 12 Unnatural Nucleoside Analogs for Antisense Therapy 403 Punit P. Seth and Eric E. Swayze 12.1 Nature Uses Nucleic Acid Polymers for Storage, Transfer, Synthesis, and Regulation of Genetic Information 403 12.2 The Antisense Approach to Drug Discovery 404 12.3 The Medicinal Chemistry Approach to Oligonucleotide Drugs 406 12.4 Structural Features of DNA and RNA Duplexes 407 12.5 Improving Binding Affinity of Oligonucleotides by Structural Mimicry of RNA 410 12.5.1 20-Modified RNA 411 12.5.2 20,40-Bridged Nucleic Acids 414 12.5.3 Hexitol Nucleic Acids 420 12.6 Improving Binding Affinity of Oligonucleotides by Conformational Restraint of DNA the Bicyclo- and Tricyclo-DNA Class of Nucleic Acid Analogs 421 12.7 Improving Binding Affinity of Oligonucleotides by Conformational Restraint of the Phosphodiester Backbone a,b-Constrained Nucleic Acids 423 12.8 Naturally Occurring Backbone Modifications 424 12.8.1 The Phosphorothioate Modification 425 12.9 Naturally Occurring Heterocycle Modifications 426 12.9.1 5-Substituted Pyrimidine Analogs 427 12.10 Outlook 428 References 429 13 Hybrid Natural Products 441 Keisuke Suzuki and Yoshizumi Yasui 13.1 Introduction 441 13.2 Staurosporines (Amino Acid Sugar Hybrids) 444 13.2.1 Occurrence 444 13.2.2 Bioactivity 445 13.2.3 Biosynthesis 446 13.2.4 Synthesis 446 13.2.5 Medicinal Chemistry 447 13.3 Lincomycins (Amino Acid Sugar Hybrids) 448 13.3.1 Occurrence 448 13.3.2 Bioactivity 448 13.3.3 Biosynthesis 448 13.3.4 Medicinal Chemistry 449 13.4 Madindolines (Amino Acid Polyketide Hybrids) 449 13.4.1 Occurrence 449 13.4.2 Bioactivity 450 13.4.3 Synthesis 451 13.5 Kainoids (Amino Acid Terpene Hybrids) 451 13.5.1 Occurrence 451 13.5.2 Bioactivity 451 13.5.3 Biosynthesis 453 13.5.4 Synthesis 453 13.5.5 Medicinal Chemistry 453 13.6 Benanomicin Pradimicin Antibiotics (Sugar Polyketide Hybrids) 455 13.6.1 Occurrence 455 13.6.2 Bioactivity 455 13.6.3 Medicinal Chemistry 456 13.6.4 Synthesis 457 13.7 Angucyclines (Sugar Polyketide Hybrids) 457 13.7.1 Occurrence and Biosynthesis 457 13.7.2 Bioactivity 459 13.7.3 Synthesis 460 13.8 Furaquinocins (Polyketide Terpene Hybrids) 462 13.8.1 Occurrence 462 13.8.2 Biosynthesis 464 13.8.3 Synthesis 464 13.9 Conclusions 467 References 467 Part Four Natural Products as Pharmacological Tools 473 14 Rethinking the Role of Natural Products: Function-Oriented Synthesis, Bryostatin, and Bryologs 475 Paul A. Wender, Alison C. Donnelly, Brian A. Loy, Katherine E. Near, and Daryl Staveness 14.1 Introduction 475 14.2 Introduction to Function-Oriented Synthesis 476 14.2.1 Representative Examples of Function-Oriented Synthesis 478 14.3 Introduction to Bryostatin 489 14.4 Bryostatin Total Syntheses 493 14.4.1 Total Syntheses of Bryostatins 2, 3, and 7 (1990 2000) 493 14.4.2 Total Synthesis of Bryostatin 16 (2008) 494 14.4.3 Total Synthesis of Bryostatin 1 (2011) 495 14.4.4 Total Synthesis of Bryostatin 9 (2011) 495 14.4.5 Total Synthesis of Bryostatin 7 (2011) 495 14.5 Application of FOS to the Bryostatin Scaffold 496 14.5.1 Initial Pharmacophoric Investigations on the Bryostatin Scaffold 498 14.5.2 Design of the First Synthetically Accessible Functional Bryostatin Analogs 500 14.5.3 Initial Preclinical Investigations of Functional Bryostatin Analogs 508 14.5.4 Des-A-Ring Analogs 510 14.5.5 C13-Functionalized Analogs 514 14.5.6 B-Ring Dioxolane Analog 516 14.5.7 C20 Analogs 518 14.5.8 C7 Analogs 520 14.5.9 A-Ring Functionalized Bryostatin Analogs 522 14.5.10 New Methodology: Prins-Driven Macrocyclization Toward B-Ring Pyran Analogs 527 14.5.11 A-Ring Functionalized Analogs and Induction of Latent HIV Expression 529 14.6 Conclusions 533 References 533 15 Cyclopamine and Congeners 545 Philipp Heretsch and Athanassios Giannis 15.1 Introduction 545 15.2 The Discovery of Cyclopamine 545 15.3 Accessibility of Cyclopamine 547 15.4 The Hedgehog Signaling Pathway 549 15.5 Medical Relevance of Cyclopamine and the Hedgehog Signaling Pathway 551 15.5.1 Models of Cancer Involving the Hedgehog Signaling Pathway 551 15.5.2 Hedgehog Signaling Pathway Inhibitors for the Treatment of Pancreatic Cancer, Myelofibrosis, and Chondrosarcoma 552 15.5.3 Prodrugs of Cyclopamine 555 15.6 Further Modulators of the Hedgehog Signaling Pathway 556 15.7 Summary and Outlook 558 References 558 Part Five Nature: The Provider, the Enticer, and the Healer 565 16 Hybrids, Congeners, Mimics, and Constrained Variants Spanning 30 Years of Natural Products Chemistry: A Personal Retrospective 567 Stephen Hanessian 16.1 Introduction 567 16.2 Structure-Based Organic Synthesis 570 16.3 Nucleosides 572 16.3.1 Quantamycin 572 16.3.2 Malayamycin A 573 16.3.3 Hydantocidin 573 16.4 b-Lactams 576 16.4.1 Analog Design 576 16.4.2 Unnatural b-Lactams 577 16.5 Morphinomimetics 579 16.6 Histone Deacetylase Inhibitors 580 16.6.1 Acyclic Inhibitors 581 16.6.2 Macrocyclic Inhibitors 582 16.7 Pactamycin Analogs 583 16.8 Aeruginosins: From Natural Products to Achiral Analogs 586 16.8.1 Structure-Based Hybrids and Truncated Analogs 586 16.8.2 Constrained Peptidomimetics 589 16.8.3 Achiral Inhibitors 589 16.9 Avermectin B1a and Bafilomycin A1 591 16.10 Bafilomycin A1 592 16.11 3-N,N-Dimethylamino Lincomycin 594 16.12 Oxazolidinone Ketolide Mimetics 595 16.13 Epilogue 596 References 598 Index 611