Bioactive Natural Products Chemistry and Biology

Natural compounds, which have evolved their function over millions of years, are often more efficient than man-made compounds if a specific biological activity is needed, e.g. as an enzyme inhibitor or as a toxin to kill a cancer cell.

This book comprising of sixteen technical chapters, highlights the chemical and biological aspects of potential natural products with an intention of unravelling their pharmaceutical applicability in modern drug discovery processes.

Key features:

• Covers the synthesis, semi-synthesis and also biosynthesis of potentially bioactive natural products
• Features chemical and biological advances in naturally occurring organic compounds describing their chemical transformations, mode of actions, and structure-activity relationships
• 40 expert scientists from around the world report their latest findings and outline future opportunities for the development of novel and highly potent drugs based on natural products operating at the interface of chemistry and biology
• Forward-looking: Addresses opportunities and cutting-edge developments rather than well-documented basic knowledge, pinpoints current trends and future directions in this rapidly-evolving field
• Application-oriented: Throughout the book, the focus is on actual and potential applications in pharmacology and biotechnology

This book is an essential resource for natural products chemists, medicinal chemists, biotechnologists, biochemists, pharmacologists, as well as the pharmaceutical and biotechnological industries.

Foreword VII

Preface XXI

About the Editor XXV

List of Contributors XXVII

1 An Overview 1
Goutam Brahmachari

2 Use of Chemical Genomics to Investigate the Mechanism of Action for Inhibitory Bioactive Natural Compounds 9
Daniel Burnside, Houman Moteshareie, Imelda G. Marquez, Mohsen Hooshyar, BahramSamanfar, Kristina Shostak, Katayoun Omidi, Harry E. Peery,Myron L. Smith, and Ashkan Golshani

2.1 Introduction: Antibiotic Resistance and the Use of Natural Products as a Source for Novel Antimicrobials 9

2.2 Chemical Genetics and Genomics 10

2.3 Development of GDA Technology 11

2.3.1 The Use of Gene Deletion Arrays (GDAs) to Investigate MOA 12

2.3.2 Chemical Genetic Interactions 12

2.3.3 Quantifying Genetic and Chemical Genetic Interactions 14

2.3.4 Data Analysis 15

2.3.5 Platforms for Chemical Genomic GDA Studies 17

2.3.6 Why Screen Natural Products in GDAs? 19

2.3.7 Successful Applications of GDA Technology 21

2.4 Concluding Remarks 22

Abbreviations 24

References 24

3 High-Throughput Drug Screening Based on Cancer Signaling in Natural Product Screening 33
Xinxin Zhang, Yuping Du, and Jinbo Yang

3.1 Introduction 33

3.2 Cancer Signaling Pathways with Their Own Drug Screening Assays in HTS 35

3.2.1 β-Galactosidase Enzyme Complementation Assays for EGFR Signaling Drug Screening 35

3.2.2 Fluorescence Superquenching Assays for PI3Ks Signaling Drug Screening 35

3.2.3 TOP Flash Reporter Gene Assays forWnt Signaling Drug Screening 36

3.2.4 Luciferase Reporter Gene Assays for STATs Signaling Drug Screening 37

3.3 Concluding Remarks 37

Abbreviations 38

References 38

4 Immunosuppressants: Remarkable Microbial Products 43
Preeti Vaishnav, Young J. Yoo, Yeo J. Yoon, and Arnold L. Demain

4.1 Introduction 43

4.2 Discovery 44

4.3 Mode of Action 47

4.4 Biosynthesis 49

4.4.1 Acetate, Propionate, Butyrate, Methionine, and Valine as Precursors of the Macrolide Rings of Sirolimus, Ascomycin, and Tacrolimus 49

4.4.2 Pipecolate Moiety of the Macrolide Ring of Sirolimus, Ascomycin, and Tacrolimus 52

4.4.3 The Final Step in Biosynthesis of Ascomycins and Tacrolimus 55

4.4.4 Formation of the Substituted Cyclohexyl Moiety of Sirolimus, Tacrolimus, and Ascomycins 58

4.4.5 Biosynthesis of Cyclosporin 61

4.5 Genetics and Strain Improvement 63

4.6 Fermentation and Nutritional Studies 65

4.7 Other Activities of Immunosuppressants 69

4.8 Concluding Remarks 71

Acknowledgments 72

References 72

5 Activators and Inhibitors of ADAM-10 for Management of Cancer and Alzheimer’s Disease 83
Prajakta Kulkarni, Manas K. Haldar, and Sanku Mallik

5.1 Introduction to ADAM Family of Enzymes 83

5.2 ADAM-10 Structure and Physiological Roles 85

5.3 Pathological Significance 85

5.3.1 Modulating ADAM Activity in Neurodegeneration 85

5.3.2 ADAM-10 in Cancer Pathology 86

5.4 ADAM-10 as Potential Drug Target 87

5.5 Synthetic Inhibitors of ADAM-10 88

5.6 Natural Products as Activators and Inhibitors for ADAM-10 92

5.7 Natural Products as ADAM-10 Activators 93

5.7.1 Ginsenoside R 94

5.7.2 Curcuma longa 94

5.7.3 Ginkgo biloba 95

5.7.4 Green Tea 95

5.8 Natural Products as ADAM-10 Inhibitors 96

5.8.1 Triptolide 96

5.8.1.1 Novel Derivatives and Carriers of Triptolide 98

5.9 Concluding Remarks 99

Abbreviations 99

References 99

6 Structure and Biological Activity of Polyether Ionophores and Their Semisynthetic Derivatives 107
Micha³ Antoszczak, Jacek Rutkowski, and Adam Huczy´nski

6.1 Introduction 107

6.2 Structures of Polyether Ionophores and Their Derivatives 108

6.2.1 Monensin and Its Derivatives 112

6.2.2 Salinomycin and Its Derivatives 117

6.2.3 Lasalocid Acid A and Its Derivatives 118

6.2.4 Other Polyether Ionophores 125

6.2.4.1 Ionophores with Monensin Skeleton 125

6.2.4.2 Polyether Ionophores with Dianemycin Skeleton 126

6.3 Chemical Properties of Polyether Ionophores and Their Derivatives 130

6.3.1 Complexes of Ionophores with Metal Cations 130

6.3.2 Mechanism of Cation Transport 132

6.4 Biological Activity 133

6.4.1 Antibacterial Activity of Polyether Antibiotics and Their Derivatives 135

6.4.2 Antifungal Activity of Polyether Antibiotics and Their Derivatives 140

6.4.3 Antiparasitic Activity of Polyether Antibiotics and Their Derivatives 141

6.4.4 Antiviral Activity of Polyether Antibiotics 144

6.4.5 Anticancer Activity of Polyether Antibiotics and Their Derivatives 145

6.5 Concluding Remarks 153

Abbreviations 154

References 155

7 Bioactive Flavaglines: Synthesis and Pharmacology 171
Christine Basmadjian, Qian Zhao, Armand de Gramont, Maria Serova, Sandrine Faivre, Eric Raymond, Stephan Vagner, Caroline Robert, Canan G. Nebigil, and Laurent Désaubry

7.1 Introduction 171

7.2 Biosynthetic Aspects 172

7.3 Synthesis of Flavaglines 174

7.3.1 Chemical Syntheses 174

7.3.2 Biomimetic Synthesis of Flavaglines 179

7.3.3 Synthesis of Silvestrol (6) 182

7.4 Pharmacological Properties of Flavaglines 184

7.4.1 Anticancer Activity 184

7.4.2 Anti-inflammatory and Immunosuppressant Activities 190

7.4.3 Cytoprotective Activity 190

7.4.4 Antimalarial Activities 191

7.5 Structure–Activity Relationships (SARs) 192

7.6 Concluding Remarks 192

Abbreviations 193

References 194

8 Beneficial Effect of Naturally Occurring Antioxidants against Oxidative Stress–Mediated Organ Dysfunctions 199
Pabitra B. Pal, Shatadal Ghosh, and Parames C. Sil

8.1 Introduction 199

8.2 Oxidative Stress and Antioxidants 200

8.2.1 Mangiferin and Its Beneficial Properties 200

8.2.1.1 Antioxidant Activity of Mangiferin 200

8.2.1.2 Anti-inflammatory Activity of Mangiferin 201

8.2.1.3 Immunomodulatory Effect 202

8.2.1.4 Antidiabetic Activity 203

8.2.1.5 Iron Complexing Activity of Mangiferin 205

8.2.1.6 Mangiferin Protects against Mercury-Induced Toxicity 205

8.2.1.7 Mangiferin Protects Murine Liver against Pb(II)–Induced Hepatic Damage 206

8.2.2 Arjunolic Acid 207

8.2.2.1 Cardioprotective Effects of Arjunolic Acid 208

8.2.2.2 Antidiabetic Activity 211

8.2.2.3 Arjunolic Acid Protects Organs from Acetaminophen (APAP)-Induced Toxicity 211

8.2.2.4 Arjunolic Acid Protects Liver from Sodium Fluoride-Induced Toxicity 212

8.2.2.5 Protection against Arsenic-Induced Toxicity 212

8.2.2.6 Mechanism of Action of Arjunolic Acid 214

8.2.3 Baicalein 214

8.2.3.1 Baicalein Protects Human Melanocytes from H2O2-Induced Apoptosis 215

8.2.3.2 Protection against Doxorubicin-Induced Cardiotoxicity 215

8.2.4 Silymarin 216

8.2.4.1 Physicochemical and Pharmacokinetic Properties of Silymarin 216

8.2.4.2 Metabolism of Silymarin 217

8.2.4.3 Antioxidant Activity of Silymarin 217

8.2.4.4 Protective Effect of Silydianin against Reactive Oxygen Species 219

8.2.4.5 Diabetes and Silymarin 219

8.2.4.6 Silibinin Protects H9c2 Cardiac Cells from Oxidative Stress 219

8.2.4.7 Silymarin Protects Liver from Doxorubicin-Induced Oxidative Damage 220

8.2.4.8 Silymarin and Hepatoprotection 220

8.2.4.9 Stimulation of Liver Regeneration 221

8.2.5 Curcumin 221

8.2.5.1 Chemical Composition of Turmeric 222

8.2.5.2 Metabolism of Curcumin 222

8.2.5.3 Antioxidant Activity of Curcumin 222

8.2.5.4 Diabetes and Curcumin 225

8.2.5.5 Efficacy of Biodegradable Curcumin Nanoparticles in Delaying Cataract in Diabetic Rat Model 226

8.3 Concluding Remarks 227

Abbreviations 227

References 228

9 Isoquinoline Alkaloids and Their Analogs: Nucleic Acid and Protein Binding Aspects, and Therapeutic Potential for Drug Design 241
Gopinatha S. Kumar

9.1 Introduction 241

9.2 Isoquinoline Alkaloids and Their Analogs 243

9.2.1 Berberine 243

9.2.1.1 Interaction of Berberine with Deoxyribonucleic Acids 244

9.2.1.2 DNA Binding of Berberine Analogs 245

9.2.1.3 Binding of Berberine and Analogs to Polymorphic DNA Conformations 248

9.2.1.4 Interaction of Berberine and Analogs with Ribonucleic Acids 253

9.2.1.5 Interaction of Berberine and Analogs with Proteins 258

9.2.2 Palmatine 260

9.2.2.1 Interaction of Palmatine and Analogs to Deoxyribonucleic Acids 261

9.2.2.2 Interaction of Palmatine with RNA 262

9.2.2.3 Interactions of Palmatine with Proteins 264

9.2.3 Other Isoquinoline Alkaloids: Jatrorrhizine, Copticine, and Analogs – DNA/RNA and Protein Interactions 266

9.3 Concluding Remarks 267

Acknowledgments 268

Abbreviations 268

References 269

10 The Potential of Peptides and Depsipeptides from Terrestrial and Marine Organisms in the Fight against Human Protozoan Diseases 279
Jean Fotie

10.1 Introduction 279

10.2 Antiprotozoan Peptides and Depsipeptides of Natural Origin and Their Synthetic Analogs 281

10.2.1 Apicidins 281

10.2.2 Almiramides and Dragonamides 282

10.2.3 Balgacyclamides 285

10.2.4 Beauvericins and Allobeauvericin 286

10.2.5 Aerucyclamides 286

10.2.6 Chondramides and Jaspamides 288

10.2.7 Enniatins and Beauvenniatins 289

10.2.8 Gallinamide A, Dolastatin 10 and 15, and Symplostatin 4 290

10.2.9 Hirsutatins and Hirsutellides 291

10.2.10 Alamethicin 292

10.2.11 Gramicidins 293

10.2.12 Kahalalides 294

10.2.13 Lagunamides 295

10.2.14 Paecilodepsipeptides 295

10.2.15 Pullularins 296

10.2.16 Szentiamide 297

10.2.17 Venturamides 297

10.2.18 Viridamides 298

10.2.19 Antiamoebin I 299

10.2.20 Efrapeptins 299

10.2.21 Valinomycin 300

10.2.22 Cyclosporins 300

10.2.23 Cyclolinopeptides 301

10.2.24 Cycloaspeptides 302

10.2.25 Mollamides 302

10.2.26 Tsushimycin 303

10.2.27 Leucinostatins 304

10.2.28 Cardinalisamides 304

10.2.29 Symplocamide A 305

10.2.30 Xenobactin 305

10.3 Concluding Remarks 306

Abbreviations 307

References 307

11 Sesquiterpene Lactones: A Versatile Class of Structurally Diverse Natural Products and Their Semisynthetic Analogs as Potential Anticancer Agents 321
Devdutt Chaturvedi, Parmesh Kumar Dwivedi, and Mamta Mishra

11.1 Introduction: Structural Features and Natural Distribution 321

11.2 Anticancer Activity of Sesquiterpenes Lactones 323

11.2.1 Costunolide and Analogs 324

11.2.2 Parthenolide and Analogs 328

11.2.3 Helenalin and Analogs 331

11.2.4 Artemisinin and Its Derivatives 332

11.2.5 Tourneforin and Its Derivatives 333

11.2.6 Eupalinin 333

11.2.7 Inuviscolide and Related Compounds 334

11.2.8 Japonicones 335

11.2.9 Isoalantolactone and Related Compounds 335

11.2.10 6-O-Angeloylenolin 336

11.2.11 Miscellaneous STLs Under Different Classes 336

11.2.11.1 Guaianolides 336

11.2.11.2 Pseudoguaianolides 339

11.2.11.3 Eudesmanolides 339

11.2.11.4 Germacranolide 340

11.2.11.5 Other Anticancer Sesquiterpene Lactones 340

11.3 Structure–Activity Relationships (SARs) of Sesquiterpenes Lactones 340

11.4 Concluding Remarks 341

Acknowledgments 342

Abbreviations 342

References 342

12 Naturally Occurring Calanolides: Chemistry and Biology 349
Goutam Brahmachari

12.1 Introduction 349

12.2 Naturally Occurring Calanolides: Structures and Physical Properties 350

12.3 Anti-HIV and Antituberculosis Potential of Calanolides 350

12.3.1 Anti-HIV Potential of Calanolides 350

12.3.2 Studies on Structure–Activity Relationships (SARs) of Calanolides 355

12.3.3 Antituberculosis Potential of Calanolides and Related Derivatives 357

12.4 Total Syntheses of Calanolides 360

12.5 Concluding Remarks 369

Acknowledgment and Disclosure 370

Abbreviations 370

References 371

13 Selective Estrogen ReceptorModulators (SERMs) from Plants 375
Divya Lakshmanan Mangalath and Chittalakkottu Sadasivan

13.1 Introduction 375

13.2 Structure of Estrogen Receptor 376

13.3 Estrogen Receptor Signaling 377

13.4 Selective Estrogen Receptor Modulators from Plants 379

13.5 Molecular Basis of the Distinct SERM Action 381

13.6 SERMs in the Treatment of Estrogen-Mediated Cancers 383

13.7 Concluding Remarks 383

Abbreviations 384

References 384

14 Introduction to the Biosynthesis and Biological Activities of Phenylpropanoids 387
Luzia V. Modolo, Cristiane J. da Silva, Fernanda G. da Silva, Leonardo da Silva Neto, and ̂ Angelo de Fátima

14.1 Introduction 387

14.2 Biosynthesis of Phenylpropanoids 387

14.3 Some Phenylpropanoid Subclasses 392

14.3.1 Flavonoids 392

14.3.1.1 Function in Plants 392

14.3.1.2 Pharmacological Properties 393

14.3.2 Coumarins 395

14.3.2.1 Function in Plants 395

14.3.2.2 Pharmacological Properties 396

14.3.3 Stilbenes 398

14.3.3.1 Function in Plants 398

14.3.3.2 Pharmacological Properties 399

14.4 Concluding Remarks 400

Acknowledgments 400

Abbreviations 400

References 401

15 Neuropeptides: Active Neuromodulators Involved in the Pathophysiology of Suicidal Behavior and Major Affective Disorders 409
Gianluca Serafini, Daniel Lindqvist, Lena Brundin, Yogesh Dwivedi, Paolo Girardi, and Mario Amore

15.1 Introduction 409

15.2 Methods 410

15.3 Involvement of Neuropeptides in the Pathophysiology of Suicidal Behavior and Major Affective Disorders 411

15.3.1 Corticotropin-Releasing Factor 411

15.3.2 Arginine Vasopressin 412

15.3.3 Oxytocin 413

15.3.4 Galanin 415

15.3.5 Tachykinins 415

15.3.6 Neuropeptide Y 418

15.3.7 Cholecystokinin 418

15.3.8 Dynorphins 420

15.3.9 Orexin 420

15.3.10 Neurotensin 423

15.3.11 Nociceptin 424

15.3.12 Melanin-Concentrating Hormone 424

15.3.13 Neuropeptide S 425

15.4 The Association between Neuropeptides, Suicidality, and Major Affective Disorders 426

15.5 Discussion of the Main Findings 429

15.6 Concluding Remarks 431

Abbreviations 432

References 433

16 From Marine Organism to Potential Drug: Using Innovative Techniques to Identify and Characterize Novel Compounds − a Bottom-Up Approach 443
A. Jonathan Singh, Jessica J. Field, Paul H. Atkinson, Peter T. Northcote, and John H. Miller

16.1 Introduction 443

16.2 Structural Screening Approach 445

16.2.1 Case Study 1: Colensolide from Osmundaria colensoi 448

16.2.2 Case Study 2: Zampanolide from Cacospongia mycofijiensis 449

16.3 Testing for Bioactivity by Screening in Mammalian Cells 452

16.4 Chemical Genetics and Network Pharmacology in Yeast for Target Identification 455

16.5 Identification of Protein Targets by Proteomic Analysis on 2D Gels 462

16.6 Validation of Compound Targets by Biochemical Analysis 462

16.7 Next Steps in Drug Development 464

16.8 Concluding Remarks 466

Acknowledgments 467

Abbreviations 467

References 467

17 Marine Natural Products: Biodiscovery, Biodiversity, and Bioproduction 473
Miguel C. Leal and Ricardo Calado

17.1 Introduction 473

17.2 Biodiscovery: What and Where? 474

17.2.1 Taxonomic Trends 475

17.2.2 Geographical Trends 478

17.3 Biodiversity 481

17.3.1 Exploring Marine Biodiversity 481

17.3.2 Protecting Marine Biodiversity 483

17.4 From Biodiscovery to Bioproduction 484

17.5 Concluding Remarks 486

References 487

Index 491