Overview

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...
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Natural Products in Medicinal Chemistry

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Overview

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

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Editorial Reviews

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

Meet the Author

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.

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Table of 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

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