Medicinal Chemistry of Plant-Derived Natural Products
portes grátis
Medicinal Chemistry of Plant-Derived Natural Products
A Chemical Exploration of Plants as a Source of Modern Drugs
Ravina, Enrique
Wiley-VCH Verlag GmbH
06/2026
560
Dura
Inglês
9783527354948
Pré-lançamento - envio 15 a 20 dias após a sua edição
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Foreword xvii
Preface xxi
Introduction & Historical Background xxxi
Part I Carbohydrates and Natural Products related to Carbohydrates 1
1 Carbohydrates 3
1.1 Polisaccarides 3
1.1.1 Gums and Mucilages 3
1.1.2 Mucilages 6
1.2 Carbohydrates as Antidiabetic Agents 6
1.2.1 ?-Glucosidase Inhibitors in Diabetes 6
A Appendix to Chapter 1 7
A.1 Non-Carbohydrates as Antidiabetic Agents 7
A.2 Type-II Antidiabetic Agents 9
A.3 Biguanides 12
2 Natural Products Related to Carbohydrates 15
2.1 Glycosides 15
2.1.1 Introduction 15
2.2 Anthraquinone Glycoside as Laxatives 16
2.3 Phenol Glycosides 19
2.3.1 Phlorizin 19
2.4 Novel Strategy in the Treatment of Type-2 Diabetes 21
2.4.1 Glycoside Type-II Antidiabetic Agents 21
2.4.2 Gliflozins 21
2.4.3 Gliflozins and Their Cardiovascular Benefits 23
References 24
Part II Polyphenols and Related Derivatives 27
3 Polyphenols and Related Derivatives 29
3.1 Introduction 29
3.1.1 Polyphenols 29
3.2 The Biosynthetic Shikimate Pathway 30
3.2.1 Aromatic Aminoacids 30
3.2.1.1 Phenyl Propanoids 30
3.2.1.2 Gallic Acid and Tannins 30
3.2.1.3 Galls 32
3.3 Phenylpropanes 33
3.3.1 Cinnamic Acid 33
3.3.2 Balsams 34
3.3.3 Cinnamon 36
3.3.4 Essential (Volatile) Oils 36
3.3.5 Vanilla 38
3.3.6 Vanillin 40
3.4 Podophyllotoxin 41
References 44
Further Reading 44
4 Benzopyrane-Based Structures 45
4.1 Coumarins, Furochromones 45
4.2 Coumarins 45
4.2.1 Anticoagulants from Sweet Clover 45
4.3 From Plant-Derived Coumarins to Modern Non Plant-Derived 47
4.3.1 Anticoagulant Therapeutic Agents 47
4.4 Furochromones 52
4.4.1 Khellin as a Source of Coronary Dilators: Calcium Channel Blockers and Other Related Derivatives 52
4.5 BIS-Chromones as Mast Cell Stabilizers 59
4.5.1 Disodium cromoglicate. Chromolyn sodium as bronchodilator 59
4.5.2 Benzofuran Antiarrythmia 60
References 61
5 Flavonoids 63
5.1 Flavones 63
5.2 Rutin (Rutoside) 68
5.3 Quercetin 70
5.4 Tea 71
5.5 Isoflavones 72
5.6 Flavone Alkaloids and Indol-based Natural Products as Cyclic-dependent Kinase Inhibitors (CDK-Inhibitors) 74
5.6.1 Flavone Alkaloid Rohituquine, Flavopiridol and Pyrimidine-related CDK Inhibitors 74
5.6.1.1 The Cell Division Cycle 74
5.6.2 Development of CDK Inhibitors 76
5.6.2.1 Non-Plant Derived CDK Inhibitors 78
5.7 Indole-based Natural Products as Cyclic Dependent Kinase Inhibitors 83
5.7.1 Indigo and Indirubine CDK Inhibitors 83
References 88
Part III Terpenes and Isoprenoids 91
6 Terpenes and Isoprenoids 93
6.1 Terpenes 93
6.1.1 Introduction 93
6.2 Monoterpenes 95
6.3 Cannabis and cannabinoids 95
6.3.1 Cannabis 95
6.3.1.1 The Long Journey of a Controversial and Paradigmatic Plant 95
6.3.2 Cultivation 97
6.3.3 Chemistry 98
6.3.4 Terpenes in Cannabis 100
6.3.5 Cannabis as a Crude Drug 101
6.3.6 Therapeutic Cannabinoids 102
6.3.7 Cannabidiol 103
6.3.8 Endocannabinoids 105
References 107
Further Reading 108
7 Sexquiterpenes (C15) and Diterpenes (C20) 109
7.1 Sexquiterpenes: Artemisia 109
7.1.1 Diterpenes: Ginkgo 109
7.2 Santonine 109
7.3 Artemisinin 110
7.3.1 From Ancient Recipes to Modern Drugs 112
7.3.1.1 Artemisinin Production 114
7.4 Diterpenes 117
7.4.1 Ginkgolides 117
References 122
8 Diterpenes II. Taxanes 125
8.1 Taxanes: Paclitaxel, Docetaxel, Cabazitaxel 125
8.1.1 Semi-Synthesis of Taxanes 128
8.1.2 Production 130
References 133
Further Reading 133
9 Triterpenes 135
9.1 Triterpenes (C30) 135
9.2 Glycoside Pentacyclic Triterpenoid Saponines 135
9.2.1 Triterpenoid Saponin Biosynthesis 137
9.2.2 Glycyrrhizin and Glycyrrhizic Acid 139
9.2.2.1 Liquorice Root 139
9.2.3 Quillaja Saponin 141
9.3 Ginseng and Ginsenosides 142
9.3.1 Ginsenoside Biosynthesis 144
9.4 Siberiang Ginseng (Eleutherococcus) 146
9.5 Triterpene Carboxylic Acids 146
9.5.1 Betulinic Acid 147
References 148
Further Reading 149
Part IV Steroids and Plant Natural products as raw materials for Steroid production. Cardioactive Glycosides 151
10 Early Steroid Chemistry. Introduction. Sexual Hormones I 153
10.1 Steroids 153
10.1.1 Introduction 153
10.1.1.1 A brief history 153
10.1.2 Five Centuries Later... 155
10.2 Nomenclature/Structural Determination/ Stereochemistry 161
10.3 Structural Determination 162
10.3.1 Primitive Methods 162
10.4 Estranes. Steroids in Which Ring a is Aromatic 164
10.4.1 Oestrogens. Oestrone. Estradiol 164
10.5 17?-Ethinyl Oestradiol 168
10.6 Early Pharmaceutical Production of Oestrogens 171
10.6.1 Progynon B Oleosum 172
10.7 Androstanes 173
10.7.1 Androgens. Androsterone. Testosterone 173
10.7.1.1 Androsterone 173
10.7.2 Testosterone 175
A Appendix to Chapter 10 179
A.1 Urinary Hormones in Medieval China 179
References 180
Further Reading 180
11 Early Steroid Chemistry. Sexual Hormones II, Progestagens. Pregnanes 181
11.1 Progesterone. The Hormone of Pregnancy, the Corpus Luteum Hormone 181
11.2 Progesterone as a Drug. Isolation of Progesterone 181
11.2.1 Progesterone: Isolation and Structural Determination 181
11.2.2 Approaches to the Synthesis of Progesterone in Germany Before WorldWar II 183
11.2.3 Progesterone as an Active Ingredient in Gestagen Formulations 185
11.2.4 Gestagens by the Oral Route: Ethistherone, the First Step 186
11.2.5 Progesterone as Prototype of Ovulation-Inhibiting Drugs: Synthetic Progesterone Analogues: Progestins 188
11.2.6 17?-hydroxyprogesterone 188
Further Reading 191
12 Steroid Chemistry III. Steroid Starting Materials 193
12.1 Phytochemicals as Raw Materials for the Semisynthesis of Steroidal Hormones 193
12.2 Mexican 'Dioscoreas', a Major Source of Steroids 194
12.2.1 From Saponin Diosgenin to Progesterone 194
12.2.1.1 Mexican Dioscoreas and Russell E. Marker 194
12.3 Rhizome of Mexican Dioscoreas as a Source of Steroids 198
12.4 Other Dioscoreas 201
12.5 Soya-bean Oil. A Major Source of Raw Materials for the Semisynthesis of Steroid Molecules 201
12.5.1 The Phytosterol Route: From Stigmasterol to Progesterone 201
12.5.2 Stigmasterol 202
12.5.3 Physostigmine, Stigmasterol and Percy Julian 202
12.6 Stigmasterol from Crude Soya Bean 203
12.7 Progesterone from Stigmasterol. Upjohn Process (1950s-1960s) 204
12.8 Soya-bean Seed 209
References 210
Further Reading 210
13 Steroid Chemistry IV. From Oestrone to 19-Nor Steroids 211
13.1 Contraceptive Agents 211
13.1.1 19-Nor Steroids 211
13.2 Norandrostane-based Steroids. Ethisterone 211
13.2.1 Industrial Production of Oestrone by Syntex. Production of Oestrone from Diosgenin 216
13.3 Androgenic-Anabolic Agents 219
13.3.1 Gonane-based Androgens 219
A Appendix to Chapter 13 221
A.1 19-Norsteroids 221
A.1.1 Total Synthesis 221
References 223
Further Reading 223
14 Steroid Chemistry V. Corticosteroids and Analogues. Adrenal Cortical Hormones 225
14.1 Cortisone, the Glucocorticoid Hormone. The Beginnings of the Cortisone Era 225
14.1.1 Cortisone from Bile Acids 227
14.2 Cortisone from Steroidal Sapogenins 229
14.2.1 Sarmentogenin 229
14.2.2 Hecogenin 230
14.2.3 Hecogenin from Sisal 230
14.3 Cortisone from Progesterone (1955). The Commercial Synthesis of Cortisone 232
14.3.1 17?-acetoxy Progesterone 237
14.3.2 Cortexolone Diacetate 238
14.4 Adrenal Cortical Hormones 239
14.4.1 Aldosterone, the Mineralocorticoid Hormone 239
14.5 Fluoro-Corticosteroids/Unsaturation Ring A 245
14.5.1 Fluorocorticoids: Fluodrocortisone 246
14.5.2 Methodology for Introducing Fluorine in 9? 247
14.6 Unsaturation Ring A. Prednisone, Prednisolone 248
14.7 6?-Methyl Corticosteroids 249
14.7.1 Introduction of 6? Methyl Group. 6?-Methylprednisolone 249
14.7.2 Triamcinolone 250
14.8 C-16 Methylcorticosteroids 252
14.8.1 Topical Corticosteroids 253
14.9 Corticosteroids. An Approach to an End... 256
14.10 Summary 257
References 260
Further Reading 260
15 Cardioactive Glycosides 261
15.1 Cardioactive Glycosides 261
15.1.1 Digitalis and Strophantus Glycosides 261
15.2 Introduction 261
15.2.1 Congestive Heart Failure (CHF) 264
15.3 Digitalis: Chemistry and Pharmacy 266
15.3.1 The Legal Reaction 268
15.3.2 Glycosides from Digitalis lanata 271
15.4 Glycosides from Digitalis Purpurea 271
15.5 Saponins on Digitalis Leaves 273
15.6 Strophantus 274
15.6.1 Convallaria 277
15.7 Squill (White Squill) 277
15.8 Toad Venom and Bufotoxin 279
Further Reading 280
Part V Alkaloids 281
16 Aminoalkaloids. Mescal. Ephedra 283
16.1 Drugs Affecting Adrenergic (Sympathetic) Neurotransmission 283
16.1.1 Ephedrine and Adrenergic Agents 283
16.2 Mescal. Mescaline 283
16.3 Ephedra. Drugs Affecting Adrenergic (Sympathetic) Neurotransmission. Adrenergic (Sympathomimetic) Agents 284
16.3.1 Ephedrine, Adrenaline (Epinephrine) and Related Drugs 284
16.4 'Ephedra' Alkaloids and Ephedrine 286
16.4.1 Ephedra. A Brief History 288
16.5 Ephedrine versus Epinephrine (Adrenaline) 289
16.6 Adrenaline (Epinephrine) and Related Drugs. Adrenergic Agents 290
16.6.1 Adrenergic Receptors 292
16.7 Epinephrine (Adrenaline) and Ephedrine Analogues. Structure-activity Relationships 293
16.8 Short Acting ?2 Adrenoreceptor Agonists (SABAs) 295
16.8.1 Selective ?2 Adrenergic Agonists: Pure Bronchodilators 295
16.9 Long Acting Selective ?2 Adrenoceptor Agonists (LABAs) 296
References 299
A Appendix to Chapter 16 299
A.1 Photos of Ephedra Bundles, Chart Ephedrine and Ephetonin from Merck KGaA (Darmstadt) Germany 299
17 Pyridine and Piperidine Alkaloids. Areca. Capsicum 303
17.1 Arecoline and Cholinergic Agents 303
17.2 Piperine 303
17.3 Capsaicin 305
17.4 Tropolone Alkaloids. Colchicumcapsaicin 306
17.5 Colchicine 307
References 309
A Appendix to Chapter 17 310
A.1 Acetylcholine and Cholinergic Receptors 310
18 Tropane Alkaloids I. Atropa belladonna and Datura stramonium 313
18.1 Tropane Alkaloids and Anticholinergic Drugs. Bronchodilators in Asthma and COPD 313
18.1.1 Reaction of Vitali-Morin 313
18.2 Atropine Atropine as Prototype of Anticholinergic Drugs 313
18.3 Scopolamine 319
18.3.1 Production of Alkaloids 320
18.4 Tropanol Esters. Atropine as a Prototype for the Development of Anticholinergic Drugs 322
18.4.1 Mydriatics Homatropine and Tropicamide 322
18.4.2 Antispasmodic Hioscine, Butyl Bromide 323
18.4.3 Short Acting Muscarinic Antagonists (SAMAs) 324
18.4.3.1 Synthetic Anticholinergics in Asthma and COPD 324
18.4.3.2 Long-Acting Muscarinic Antagonists (LAMAs) 325
18.5 Bronchodilators in the Treatment of Asthma and COPD (see also Chapter 16, Ephedra and Adrenergic Agents) 326
18.5.1 Dual Bronchodilator Therapy 327
18.6 Asthma/Allergic Disorders. COPD 328
References 328
19 Tropane Alkaloids II Coca Leaf (Cocae folium). Cocaine and Local Anaesthetics 331
19.1 Introduction. Historical Background 331
19.2 The Chemistry of Coca Leaves 335
19.2.1 Cocaine Hydrochloride. Cocaine an Ancient Anaesthetic 338
19.3 Synthetic Local Anaesthetics 338
19.3.1 Structural Variations on Cocaine. From Cocaine to Procaine. Amino-alcohol-type Local Anaesthetics 339
19.3.1.1 Eucaines, the First 339
19.3.2 Ortoforms, Stovaine, Benzocaine and Procaine 341
19.3.3 Anilide-type Local Anaesthetics. Lidocaine and Further Developments 342
19.3.3.1 Lidocaine 342
19.3.4 Mepivacaine, Bupivacaine, Ropivacaine 346
References 348
Further Reading 348
A Appendix to Chapter 19 348
A.1 Amide-Type Local Anaesthetics as Antiarryhtmic Drugs. Other Antiarrhythmic Drugs 348
20 Isoquinoline AlkaloidsIsoquinoline Alkaloids 351
20.1 Opium, Opium Alkaloids and Their Derivatives. Morphine. Structural Variations on Morphine 351
20.1.1 Introduction 351
20.1.2 Chemical Synthesis of Isoquinolines 351
20.1.2.1 Synthesis of Bischler-Napieralski 351
20.1.2.2 Synthesis of Pictet-Spengler 352
20.2 Opium, Opium Alkaloids and Their Derivatives 354
20.3 Opium 354
20.3.1 Divinum opus est sedare dolorem Hippocrates 354
20.3.2 Papaverine 357
20.3.3 Opium in the European Pharmacopoeia 359
20.3.4 Morphine 360
20.3.5 Codeine 361
20.3.6 Thebaine 361
20.4 Structural Variations on Morphine. Morphine Fragmentation 365
20.5 Structural Variations on Morphine I. Simple Modifications 365
20.5.1 Narcotic Antagonists 365
20.6 Structural Variations on Morphine II 367
20.6.1 Rigid Opioids: Morphinans and Benzomorphans 367
20.6.1.1 Morphinans 367
20.6.1.2 Benzomorphans 368
20.7 Structural Variations on Morphine III. Flexible Opioids 370
20.7.1 4-Phenyl Piperidines. Meperidine = Pethidine 370
20.7.2 Schaumann's Postulate 371
20.8 Structural Variations on Morphine IV. 4-Phenyl Piperidines 372
20.8.1 From Meperidine to Butyrophenone Neuroleptics 372
20.8.1.1 Haloperidol 372
20.9 Structural Variations on Morphine V. 4-Phenyl Piperidines 374
20.9.1 Opioid-Based Antidiarrheals. Diphenoxilate. Loperamide 374
20.10 Structural Variations on Morphine VI. Flexible Opioids 376
20.10.1 4-Anilido-Piperidines 376
20.10.1.1 Fentanyls 376
20.11 Structural Variations on Morphine VII 378
20.11.1 Methadone 378
20.12 Structural Variations on Morphine VIII. Simplified Codeines. Flexible Opioids as Dual Acting Agents: Tramadol and Tapentadol 378
20.12.1 Tapentadol 380
References 382
Further Reading 382
21 Isoquinoline Alkaloids 383
21.1 Introduction and Historical Background 383
21.1.1 Natural Curares 385
21.1.1.1 Historical Background 385
21.1.2 Early Missionaries and Explorers 387
21.1.2.1 Father Jose Acosta S.J. 387
21.1.2.2 Father Jose Gumilla S.J. 387
21.1.3 Alexander von Humboldt and Aime Bonpland 389
21.2 Eduard Friedrich Poeppig and Schomburgk brothers 390
21.2.1 Eduard Friedrich Poeppig 390
21.2.2 Schomburgk brothers, Robert and Moritz-Richard, German-born explorers and botanists 392
21.3 The First Experimental Studies 393
21.3.1 Early Classification of Curares 393
21.3.1.1 Claude Bernard 393
21.3.1.2 Rudolf Boehm 394
21.3.1.3 Tubocurare 394
21.3.1.4 Calabash Curare 394
21.4 Botanical Sources of Curares 396
21.5 Chemistry of Curares 396
21.5.1 Curare from Chondodendron. Intocostrin (R), the First Pharmaceutical Formulation of a Curare Extract 396
21.5.2 Tubocurarine, the First Curare-Like Drug 398
21.5.3 Curares. Several Methods of Preparation 400
21.6 Tetrahydroisoquinoline-based Curare-like Agents. From Alkaloid Petaline to Synthetic Atracurium 403
21.7 Steroid-based Curare-like Agents. From Alkaloid Malouetine to Pancuronium and Other Curoniums 408
21.8 Reversal Agents of Neuromuscular Blockade: Cyclodextrins: Sugammadex Sodium 414
References 415
21 bis-Terpenoid Isoquinoline Alkaloids: Ipeca Alkaloids 417
21.1 Alkaloids from Ipeca 417
22 Amaryllidacea Alkaloids. Galantamine 419
22.1 Galantamine 419
22.2 Racemic Synthesis of Galantamine 423
22.2.1 Asymmetric Synthesis of (?) Galantamine 425
References 425
Further Reading 425
23 Indole Alkaloids. Introduction 427
23.1 Physostigmine 427
23.2 Alzheimer's Disease 430
References 432
24 Terpene Indole Alkaloids. Introduction 433
24.1 Terpene Indole Alkaloids. Antitumour Vinca Alkaloids 433
24.1.1 Vinorelbine 433
24.2 Terpene Indole Alkaloids. Reserpine 434
24.2.1 Vinorelbine 438
24.3 Reserpine 439
24.4 Terpene-Indole Alkaloids. Ergot Alkaloids. Ergotamine. Ergobasine 440
24.4.1 Ergolines 444
References 445
Further Reading 445
A Appendix to Chapter 24 445
A.1 Triptans 445
25 Quinoline Alkaloids 447
25.1 Malaria. Cinchona Bark and Quinine 447
25.1.1 From Quinine to Synthetic Antimalarials 447
25.1.2 The Plasmodium Cycle 447
25.2 Cinchona Bark 449
25.2.1 Introduction and Historical Background 449
25.3 Scientific Expeditions to the NewWorld. The Spanish Enlightenment (Eighteenth Century) 451
25.4 Cinchona Bark Alkaloids. The Chemistry of Cinchona Alkaloids. An Approach 457
25.4.1 Isolation and Production of Quinine 457
25.4.2 The Quinine Structure 459
25.4.3 Synthesis deWooward-Doering 460
25.4.4 Quinine Sulphate, Today 463
25.4.5 Quinidine Sulphate 463
25.5 From Quinine to Synthetic Antimalarials 463
25.5.1 Amino-Acridines and Amino-Quinolines 463
25.5.2 Chloroquine, Antimalarial Discovered Twice 464
References and Notes 467
A Appendix to Chapter 25 468
A.1 Synthetic Antimalarials. Antifolates 468
A.1.1 Proguanil/Cycloguanil 468
A.1.2 Atovaquone 469
26 Quinoline Alkaloids 471
26.1 Camptotheca 471
26.1.1 Camptothecine and Derivatives as Anticancer Agents 471
References 477
Further Reading 478
27 Miscellaneous 479
27.1 Cephalotaxus Alkaloids: Homoharringtonine (Omacetaxine Mepesuccinate) 479
27.2 Purine Alkaloids: Xanthines 482
References 484
Index 485
Preface xxi
Introduction & Historical Background xxxi
Part I Carbohydrates and Natural Products related to Carbohydrates 1
1 Carbohydrates 3
1.1 Polisaccarides 3
1.1.1 Gums and Mucilages 3
1.1.2 Mucilages 6
1.2 Carbohydrates as Antidiabetic Agents 6
1.2.1 ?-Glucosidase Inhibitors in Diabetes 6
A Appendix to Chapter 1 7
A.1 Non-Carbohydrates as Antidiabetic Agents 7
A.2 Type-II Antidiabetic Agents 9
A.3 Biguanides 12
2 Natural Products Related to Carbohydrates 15
2.1 Glycosides 15
2.1.1 Introduction 15
2.2 Anthraquinone Glycoside as Laxatives 16
2.3 Phenol Glycosides 19
2.3.1 Phlorizin 19
2.4 Novel Strategy in the Treatment of Type-2 Diabetes 21
2.4.1 Glycoside Type-II Antidiabetic Agents 21
2.4.2 Gliflozins 21
2.4.3 Gliflozins and Their Cardiovascular Benefits 23
References 24
Part II Polyphenols and Related Derivatives 27
3 Polyphenols and Related Derivatives 29
3.1 Introduction 29
3.1.1 Polyphenols 29
3.2 The Biosynthetic Shikimate Pathway 30
3.2.1 Aromatic Aminoacids 30
3.2.1.1 Phenyl Propanoids 30
3.2.1.2 Gallic Acid and Tannins 30
3.2.1.3 Galls 32
3.3 Phenylpropanes 33
3.3.1 Cinnamic Acid 33
3.3.2 Balsams 34
3.3.3 Cinnamon 36
3.3.4 Essential (Volatile) Oils 36
3.3.5 Vanilla 38
3.3.6 Vanillin 40
3.4 Podophyllotoxin 41
References 44
Further Reading 44
4 Benzopyrane-Based Structures 45
4.1 Coumarins, Furochromones 45
4.2 Coumarins 45
4.2.1 Anticoagulants from Sweet Clover 45
4.3 From Plant-Derived Coumarins to Modern Non Plant-Derived 47
4.3.1 Anticoagulant Therapeutic Agents 47
4.4 Furochromones 52
4.4.1 Khellin as a Source of Coronary Dilators: Calcium Channel Blockers and Other Related Derivatives 52
4.5 BIS-Chromones as Mast Cell Stabilizers 59
4.5.1 Disodium cromoglicate. Chromolyn sodium as bronchodilator 59
4.5.2 Benzofuran Antiarrythmia 60
References 61
5 Flavonoids 63
5.1 Flavones 63
5.2 Rutin (Rutoside) 68
5.3 Quercetin 70
5.4 Tea 71
5.5 Isoflavones 72
5.6 Flavone Alkaloids and Indol-based Natural Products as Cyclic-dependent Kinase Inhibitors (CDK-Inhibitors) 74
5.6.1 Flavone Alkaloid Rohituquine, Flavopiridol and Pyrimidine-related CDK Inhibitors 74
5.6.1.1 The Cell Division Cycle 74
5.6.2 Development of CDK Inhibitors 76
5.6.2.1 Non-Plant Derived CDK Inhibitors 78
5.7 Indole-based Natural Products as Cyclic Dependent Kinase Inhibitors 83
5.7.1 Indigo and Indirubine CDK Inhibitors 83
References 88
Part III Terpenes and Isoprenoids 91
6 Terpenes and Isoprenoids 93
6.1 Terpenes 93
6.1.1 Introduction 93
6.2 Monoterpenes 95
6.3 Cannabis and cannabinoids 95
6.3.1 Cannabis 95
6.3.1.1 The Long Journey of a Controversial and Paradigmatic Plant 95
6.3.2 Cultivation 97
6.3.3 Chemistry 98
6.3.4 Terpenes in Cannabis 100
6.3.5 Cannabis as a Crude Drug 101
6.3.6 Therapeutic Cannabinoids 102
6.3.7 Cannabidiol 103
6.3.8 Endocannabinoids 105
References 107
Further Reading 108
7 Sexquiterpenes (C15) and Diterpenes (C20) 109
7.1 Sexquiterpenes: Artemisia 109
7.1.1 Diterpenes: Ginkgo 109
7.2 Santonine 109
7.3 Artemisinin 110
7.3.1 From Ancient Recipes to Modern Drugs 112
7.3.1.1 Artemisinin Production 114
7.4 Diterpenes 117
7.4.1 Ginkgolides 117
References 122
8 Diterpenes II. Taxanes 125
8.1 Taxanes: Paclitaxel, Docetaxel, Cabazitaxel 125
8.1.1 Semi-Synthesis of Taxanes 128
8.1.2 Production 130
References 133
Further Reading 133
9 Triterpenes 135
9.1 Triterpenes (C30) 135
9.2 Glycoside Pentacyclic Triterpenoid Saponines 135
9.2.1 Triterpenoid Saponin Biosynthesis 137
9.2.2 Glycyrrhizin and Glycyrrhizic Acid 139
9.2.2.1 Liquorice Root 139
9.2.3 Quillaja Saponin 141
9.3 Ginseng and Ginsenosides 142
9.3.1 Ginsenoside Biosynthesis 144
9.4 Siberiang Ginseng (Eleutherococcus) 146
9.5 Triterpene Carboxylic Acids 146
9.5.1 Betulinic Acid 147
References 148
Further Reading 149
Part IV Steroids and Plant Natural products as raw materials for Steroid production. Cardioactive Glycosides 151
10 Early Steroid Chemistry. Introduction. Sexual Hormones I 153
10.1 Steroids 153
10.1.1 Introduction 153
10.1.1.1 A brief history 153
10.1.2 Five Centuries Later... 155
10.2 Nomenclature/Structural Determination/ Stereochemistry 161
10.3 Structural Determination 162
10.3.1 Primitive Methods 162
10.4 Estranes. Steroids in Which Ring a is Aromatic 164
10.4.1 Oestrogens. Oestrone. Estradiol 164
10.5 17?-Ethinyl Oestradiol 168
10.6 Early Pharmaceutical Production of Oestrogens 171
10.6.1 Progynon B Oleosum 172
10.7 Androstanes 173
10.7.1 Androgens. Androsterone. Testosterone 173
10.7.1.1 Androsterone 173
10.7.2 Testosterone 175
A Appendix to Chapter 10 179
A.1 Urinary Hormones in Medieval China 179
References 180
Further Reading 180
11 Early Steroid Chemistry. Sexual Hormones II, Progestagens. Pregnanes 181
11.1 Progesterone. The Hormone of Pregnancy, the Corpus Luteum Hormone 181
11.2 Progesterone as a Drug. Isolation of Progesterone 181
11.2.1 Progesterone: Isolation and Structural Determination 181
11.2.2 Approaches to the Synthesis of Progesterone in Germany Before WorldWar II 183
11.2.3 Progesterone as an Active Ingredient in Gestagen Formulations 185
11.2.4 Gestagens by the Oral Route: Ethistherone, the First Step 186
11.2.5 Progesterone as Prototype of Ovulation-Inhibiting Drugs: Synthetic Progesterone Analogues: Progestins 188
11.2.6 17?-hydroxyprogesterone 188
Further Reading 191
12 Steroid Chemistry III. Steroid Starting Materials 193
12.1 Phytochemicals as Raw Materials for the Semisynthesis of Steroidal Hormones 193
12.2 Mexican 'Dioscoreas', a Major Source of Steroids 194
12.2.1 From Saponin Diosgenin to Progesterone 194
12.2.1.1 Mexican Dioscoreas and Russell E. Marker 194
12.3 Rhizome of Mexican Dioscoreas as a Source of Steroids 198
12.4 Other Dioscoreas 201
12.5 Soya-bean Oil. A Major Source of Raw Materials for the Semisynthesis of Steroid Molecules 201
12.5.1 The Phytosterol Route: From Stigmasterol to Progesterone 201
12.5.2 Stigmasterol 202
12.5.3 Physostigmine, Stigmasterol and Percy Julian 202
12.6 Stigmasterol from Crude Soya Bean 203
12.7 Progesterone from Stigmasterol. Upjohn Process (1950s-1960s) 204
12.8 Soya-bean Seed 209
References 210
Further Reading 210
13 Steroid Chemistry IV. From Oestrone to 19-Nor Steroids 211
13.1 Contraceptive Agents 211
13.1.1 19-Nor Steroids 211
13.2 Norandrostane-based Steroids. Ethisterone 211
13.2.1 Industrial Production of Oestrone by Syntex. Production of Oestrone from Diosgenin 216
13.3 Androgenic-Anabolic Agents 219
13.3.1 Gonane-based Androgens 219
A Appendix to Chapter 13 221
A.1 19-Norsteroids 221
A.1.1 Total Synthesis 221
References 223
Further Reading 223
14 Steroid Chemistry V. Corticosteroids and Analogues. Adrenal Cortical Hormones 225
14.1 Cortisone, the Glucocorticoid Hormone. The Beginnings of the Cortisone Era 225
14.1.1 Cortisone from Bile Acids 227
14.2 Cortisone from Steroidal Sapogenins 229
14.2.1 Sarmentogenin 229
14.2.2 Hecogenin 230
14.2.3 Hecogenin from Sisal 230
14.3 Cortisone from Progesterone (1955). The Commercial Synthesis of Cortisone 232
14.3.1 17?-acetoxy Progesterone 237
14.3.2 Cortexolone Diacetate 238
14.4 Adrenal Cortical Hormones 239
14.4.1 Aldosterone, the Mineralocorticoid Hormone 239
14.5 Fluoro-Corticosteroids/Unsaturation Ring A 245
14.5.1 Fluorocorticoids: Fluodrocortisone 246
14.5.2 Methodology for Introducing Fluorine in 9? 247
14.6 Unsaturation Ring A. Prednisone, Prednisolone 248
14.7 6?-Methyl Corticosteroids 249
14.7.1 Introduction of 6? Methyl Group. 6?-Methylprednisolone 249
14.7.2 Triamcinolone 250
14.8 C-16 Methylcorticosteroids 252
14.8.1 Topical Corticosteroids 253
14.9 Corticosteroids. An Approach to an End... 256
14.10 Summary 257
References 260
Further Reading 260
15 Cardioactive Glycosides 261
15.1 Cardioactive Glycosides 261
15.1.1 Digitalis and Strophantus Glycosides 261
15.2 Introduction 261
15.2.1 Congestive Heart Failure (CHF) 264
15.3 Digitalis: Chemistry and Pharmacy 266
15.3.1 The Legal Reaction 268
15.3.2 Glycosides from Digitalis lanata 271
15.4 Glycosides from Digitalis Purpurea 271
15.5 Saponins on Digitalis Leaves 273
15.6 Strophantus 274
15.6.1 Convallaria 277
15.7 Squill (White Squill) 277
15.8 Toad Venom and Bufotoxin 279
Further Reading 280
Part V Alkaloids 281
16 Aminoalkaloids. Mescal. Ephedra 283
16.1 Drugs Affecting Adrenergic (Sympathetic) Neurotransmission 283
16.1.1 Ephedrine and Adrenergic Agents 283
16.2 Mescal. Mescaline 283
16.3 Ephedra. Drugs Affecting Adrenergic (Sympathetic) Neurotransmission. Adrenergic (Sympathomimetic) Agents 284
16.3.1 Ephedrine, Adrenaline (Epinephrine) and Related Drugs 284
16.4 'Ephedra' Alkaloids and Ephedrine 286
16.4.1 Ephedra. A Brief History 288
16.5 Ephedrine versus Epinephrine (Adrenaline) 289
16.6 Adrenaline (Epinephrine) and Related Drugs. Adrenergic Agents 290
16.6.1 Adrenergic Receptors 292
16.7 Epinephrine (Adrenaline) and Ephedrine Analogues. Structure-activity Relationships 293
16.8 Short Acting ?2 Adrenoreceptor Agonists (SABAs) 295
16.8.1 Selective ?2 Adrenergic Agonists: Pure Bronchodilators 295
16.9 Long Acting Selective ?2 Adrenoceptor Agonists (LABAs) 296
References 299
A Appendix to Chapter 16 299
A.1 Photos of Ephedra Bundles, Chart Ephedrine and Ephetonin from Merck KGaA (Darmstadt) Germany 299
17 Pyridine and Piperidine Alkaloids. Areca. Capsicum 303
17.1 Arecoline and Cholinergic Agents 303
17.2 Piperine 303
17.3 Capsaicin 305
17.4 Tropolone Alkaloids. Colchicumcapsaicin 306
17.5 Colchicine 307
References 309
A Appendix to Chapter 17 310
A.1 Acetylcholine and Cholinergic Receptors 310
18 Tropane Alkaloids I. Atropa belladonna and Datura stramonium 313
18.1 Tropane Alkaloids and Anticholinergic Drugs. Bronchodilators in Asthma and COPD 313
18.1.1 Reaction of Vitali-Morin 313
18.2 Atropine Atropine as Prototype of Anticholinergic Drugs 313
18.3 Scopolamine 319
18.3.1 Production of Alkaloids 320
18.4 Tropanol Esters. Atropine as a Prototype for the Development of Anticholinergic Drugs 322
18.4.1 Mydriatics Homatropine and Tropicamide 322
18.4.2 Antispasmodic Hioscine, Butyl Bromide 323
18.4.3 Short Acting Muscarinic Antagonists (SAMAs) 324
18.4.3.1 Synthetic Anticholinergics in Asthma and COPD 324
18.4.3.2 Long-Acting Muscarinic Antagonists (LAMAs) 325
18.5 Bronchodilators in the Treatment of Asthma and COPD (see also Chapter 16, Ephedra and Adrenergic Agents) 326
18.5.1 Dual Bronchodilator Therapy 327
18.6 Asthma/Allergic Disorders. COPD 328
References 328
19 Tropane Alkaloids II Coca Leaf (Cocae folium). Cocaine and Local Anaesthetics 331
19.1 Introduction. Historical Background 331
19.2 The Chemistry of Coca Leaves 335
19.2.1 Cocaine Hydrochloride. Cocaine an Ancient Anaesthetic 338
19.3 Synthetic Local Anaesthetics 338
19.3.1 Structural Variations on Cocaine. From Cocaine to Procaine. Amino-alcohol-type Local Anaesthetics 339
19.3.1.1 Eucaines, the First 339
19.3.2 Ortoforms, Stovaine, Benzocaine and Procaine 341
19.3.3 Anilide-type Local Anaesthetics. Lidocaine and Further Developments 342
19.3.3.1 Lidocaine 342
19.3.4 Mepivacaine, Bupivacaine, Ropivacaine 346
References 348
Further Reading 348
A Appendix to Chapter 19 348
A.1 Amide-Type Local Anaesthetics as Antiarryhtmic Drugs. Other Antiarrhythmic Drugs 348
20 Isoquinoline AlkaloidsIsoquinoline Alkaloids 351
20.1 Opium, Opium Alkaloids and Their Derivatives. Morphine. Structural Variations on Morphine 351
20.1.1 Introduction 351
20.1.2 Chemical Synthesis of Isoquinolines 351
20.1.2.1 Synthesis of Bischler-Napieralski 351
20.1.2.2 Synthesis of Pictet-Spengler 352
20.2 Opium, Opium Alkaloids and Their Derivatives 354
20.3 Opium 354
20.3.1 Divinum opus est sedare dolorem Hippocrates 354
20.3.2 Papaverine 357
20.3.3 Opium in the European Pharmacopoeia 359
20.3.4 Morphine 360
20.3.5 Codeine 361
20.3.6 Thebaine 361
20.4 Structural Variations on Morphine. Morphine Fragmentation 365
20.5 Structural Variations on Morphine I. Simple Modifications 365
20.5.1 Narcotic Antagonists 365
20.6 Structural Variations on Morphine II 367
20.6.1 Rigid Opioids: Morphinans and Benzomorphans 367
20.6.1.1 Morphinans 367
20.6.1.2 Benzomorphans 368
20.7 Structural Variations on Morphine III. Flexible Opioids 370
20.7.1 4-Phenyl Piperidines. Meperidine = Pethidine 370
20.7.2 Schaumann's Postulate 371
20.8 Structural Variations on Morphine IV. 4-Phenyl Piperidines 372
20.8.1 From Meperidine to Butyrophenone Neuroleptics 372
20.8.1.1 Haloperidol 372
20.9 Structural Variations on Morphine V. 4-Phenyl Piperidines 374
20.9.1 Opioid-Based Antidiarrheals. Diphenoxilate. Loperamide 374
20.10 Structural Variations on Morphine VI. Flexible Opioids 376
20.10.1 4-Anilido-Piperidines 376
20.10.1.1 Fentanyls 376
20.11 Structural Variations on Morphine VII 378
20.11.1 Methadone 378
20.12 Structural Variations on Morphine VIII. Simplified Codeines. Flexible Opioids as Dual Acting Agents: Tramadol and Tapentadol 378
20.12.1 Tapentadol 380
References 382
Further Reading 382
21 Isoquinoline Alkaloids 383
21.1 Introduction and Historical Background 383
21.1.1 Natural Curares 385
21.1.1.1 Historical Background 385
21.1.2 Early Missionaries and Explorers 387
21.1.2.1 Father Jose Acosta S.J. 387
21.1.2.2 Father Jose Gumilla S.J. 387
21.1.3 Alexander von Humboldt and Aime Bonpland 389
21.2 Eduard Friedrich Poeppig and Schomburgk brothers 390
21.2.1 Eduard Friedrich Poeppig 390
21.2.2 Schomburgk brothers, Robert and Moritz-Richard, German-born explorers and botanists 392
21.3 The First Experimental Studies 393
21.3.1 Early Classification of Curares 393
21.3.1.1 Claude Bernard 393
21.3.1.2 Rudolf Boehm 394
21.3.1.3 Tubocurare 394
21.3.1.4 Calabash Curare 394
21.4 Botanical Sources of Curares 396
21.5 Chemistry of Curares 396
21.5.1 Curare from Chondodendron. Intocostrin (R), the First Pharmaceutical Formulation of a Curare Extract 396
21.5.2 Tubocurarine, the First Curare-Like Drug 398
21.5.3 Curares. Several Methods of Preparation 400
21.6 Tetrahydroisoquinoline-based Curare-like Agents. From Alkaloid Petaline to Synthetic Atracurium 403
21.7 Steroid-based Curare-like Agents. From Alkaloid Malouetine to Pancuronium and Other Curoniums 408
21.8 Reversal Agents of Neuromuscular Blockade: Cyclodextrins: Sugammadex Sodium 414
References 415
21 bis-Terpenoid Isoquinoline Alkaloids: Ipeca Alkaloids 417
21.1 Alkaloids from Ipeca 417
22 Amaryllidacea Alkaloids. Galantamine 419
22.1 Galantamine 419
22.2 Racemic Synthesis of Galantamine 423
22.2.1 Asymmetric Synthesis of (?) Galantamine 425
References 425
Further Reading 425
23 Indole Alkaloids. Introduction 427
23.1 Physostigmine 427
23.2 Alzheimer's Disease 430
References 432
24 Terpene Indole Alkaloids. Introduction 433
24.1 Terpene Indole Alkaloids. Antitumour Vinca Alkaloids 433
24.1.1 Vinorelbine 433
24.2 Terpene Indole Alkaloids. Reserpine 434
24.2.1 Vinorelbine 438
24.3 Reserpine 439
24.4 Terpene-Indole Alkaloids. Ergot Alkaloids. Ergotamine. Ergobasine 440
24.4.1 Ergolines 444
References 445
Further Reading 445
A Appendix to Chapter 24 445
A.1 Triptans 445
25 Quinoline Alkaloids 447
25.1 Malaria. Cinchona Bark and Quinine 447
25.1.1 From Quinine to Synthetic Antimalarials 447
25.1.2 The Plasmodium Cycle 447
25.2 Cinchona Bark 449
25.2.1 Introduction and Historical Background 449
25.3 Scientific Expeditions to the NewWorld. The Spanish Enlightenment (Eighteenth Century) 451
25.4 Cinchona Bark Alkaloids. The Chemistry of Cinchona Alkaloids. An Approach 457
25.4.1 Isolation and Production of Quinine 457
25.4.2 The Quinine Structure 459
25.4.3 Synthesis deWooward-Doering 460
25.4.4 Quinine Sulphate, Today 463
25.4.5 Quinidine Sulphate 463
25.5 From Quinine to Synthetic Antimalarials 463
25.5.1 Amino-Acridines and Amino-Quinolines 463
25.5.2 Chloroquine, Antimalarial Discovered Twice 464
References and Notes 467
A Appendix to Chapter 25 468
A.1 Synthetic Antimalarials. Antifolates 468
A.1.1 Proguanil/Cycloguanil 468
A.1.2 Atovaquone 469
26 Quinoline Alkaloids 471
26.1 Camptotheca 471
26.1.1 Camptothecine and Derivatives as Anticancer Agents 471
References 477
Further Reading 478
27 Miscellaneous 479
27.1 Cephalotaxus Alkaloids: Homoharringtonine (Omacetaxine Mepesuccinate) 479
27.2 Purine Alkaloids: Xanthines 482
References 484
Index 485
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plant drug design; plant drug discovery; plant drug design; natural drug design; natural drug discovery; plant drug discovery; plant pharmaceuticals; natural pharmaceuticals; polyphenols; terpenes; steroids; alkaloids
Foreword xvii
Preface xxi
Introduction & Historical Background xxxi
Part I Carbohydrates and Natural Products related to Carbohydrates 1
1 Carbohydrates 3
1.1 Polisaccarides 3
1.1.1 Gums and Mucilages 3
1.1.2 Mucilages 6
1.2 Carbohydrates as Antidiabetic Agents 6
1.2.1 ?-Glucosidase Inhibitors in Diabetes 6
A Appendix to Chapter 1 7
A.1 Non-Carbohydrates as Antidiabetic Agents 7
A.2 Type-II Antidiabetic Agents 9
A.3 Biguanides 12
2 Natural Products Related to Carbohydrates 15
2.1 Glycosides 15
2.1.1 Introduction 15
2.2 Anthraquinone Glycoside as Laxatives 16
2.3 Phenol Glycosides 19
2.3.1 Phlorizin 19
2.4 Novel Strategy in the Treatment of Type-2 Diabetes 21
2.4.1 Glycoside Type-II Antidiabetic Agents 21
2.4.2 Gliflozins 21
2.4.3 Gliflozins and Their Cardiovascular Benefits 23
References 24
Part II Polyphenols and Related Derivatives 27
3 Polyphenols and Related Derivatives 29
3.1 Introduction 29
3.1.1 Polyphenols 29
3.2 The Biosynthetic Shikimate Pathway 30
3.2.1 Aromatic Aminoacids 30
3.2.1.1 Phenyl Propanoids 30
3.2.1.2 Gallic Acid and Tannins 30
3.2.1.3 Galls 32
3.3 Phenylpropanes 33
3.3.1 Cinnamic Acid 33
3.3.2 Balsams 34
3.3.3 Cinnamon 36
3.3.4 Essential (Volatile) Oils 36
3.3.5 Vanilla 38
3.3.6 Vanillin 40
3.4 Podophyllotoxin 41
References 44
Further Reading 44
4 Benzopyrane-Based Structures 45
4.1 Coumarins, Furochromones 45
4.2 Coumarins 45
4.2.1 Anticoagulants from Sweet Clover 45
4.3 From Plant-Derived Coumarins to Modern Non Plant-Derived 47
4.3.1 Anticoagulant Therapeutic Agents 47
4.4 Furochromones 52
4.4.1 Khellin as a Source of Coronary Dilators: Calcium Channel Blockers and Other Related Derivatives 52
4.5 BIS-Chromones as Mast Cell Stabilizers 59
4.5.1 Disodium cromoglicate. Chromolyn sodium as bronchodilator 59
4.5.2 Benzofuran Antiarrythmia 60
References 61
5 Flavonoids 63
5.1 Flavones 63
5.2 Rutin (Rutoside) 68
5.3 Quercetin 70
5.4 Tea 71
5.5 Isoflavones 72
5.6 Flavone Alkaloids and Indol-based Natural Products as Cyclic-dependent Kinase Inhibitors (CDK-Inhibitors) 74
5.6.1 Flavone Alkaloid Rohituquine, Flavopiridol and Pyrimidine-related CDK Inhibitors 74
5.6.1.1 The Cell Division Cycle 74
5.6.2 Development of CDK Inhibitors 76
5.6.2.1 Non-Plant Derived CDK Inhibitors 78
5.7 Indole-based Natural Products as Cyclic Dependent Kinase Inhibitors 83
5.7.1 Indigo and Indirubine CDK Inhibitors 83
References 88
Part III Terpenes and Isoprenoids 91
6 Terpenes and Isoprenoids 93
6.1 Terpenes 93
6.1.1 Introduction 93
6.2 Monoterpenes 95
6.3 Cannabis and cannabinoids 95
6.3.1 Cannabis 95
6.3.1.1 The Long Journey of a Controversial and Paradigmatic Plant 95
6.3.2 Cultivation 97
6.3.3 Chemistry 98
6.3.4 Terpenes in Cannabis 100
6.3.5 Cannabis as a Crude Drug 101
6.3.6 Therapeutic Cannabinoids 102
6.3.7 Cannabidiol 103
6.3.8 Endocannabinoids 105
References 107
Further Reading 108
7 Sexquiterpenes (C15) and Diterpenes (C20) 109
7.1 Sexquiterpenes: Artemisia 109
7.1.1 Diterpenes: Ginkgo 109
7.2 Santonine 109
7.3 Artemisinin 110
7.3.1 From Ancient Recipes to Modern Drugs 112
7.3.1.1 Artemisinin Production 114
7.4 Diterpenes 117
7.4.1 Ginkgolides 117
References 122
8 Diterpenes II. Taxanes 125
8.1 Taxanes: Paclitaxel, Docetaxel, Cabazitaxel 125
8.1.1 Semi-Synthesis of Taxanes 128
8.1.2 Production 130
References 133
Further Reading 133
9 Triterpenes 135
9.1 Triterpenes (C30) 135
9.2 Glycoside Pentacyclic Triterpenoid Saponines 135
9.2.1 Triterpenoid Saponin Biosynthesis 137
9.2.2 Glycyrrhizin and Glycyrrhizic Acid 139
9.2.2.1 Liquorice Root 139
9.2.3 Quillaja Saponin 141
9.3 Ginseng and Ginsenosides 142
9.3.1 Ginsenoside Biosynthesis 144
9.4 Siberiang Ginseng (Eleutherococcus) 146
9.5 Triterpene Carboxylic Acids 146
9.5.1 Betulinic Acid 147
References 148
Further Reading 149
Part IV Steroids and Plant Natural products as raw materials for Steroid production. Cardioactive Glycosides 151
10 Early Steroid Chemistry. Introduction. Sexual Hormones I 153
10.1 Steroids 153
10.1.1 Introduction 153
10.1.1.1 A brief history 153
10.1.2 Five Centuries Later... 155
10.2 Nomenclature/Structural Determination/ Stereochemistry 161
10.3 Structural Determination 162
10.3.1 Primitive Methods 162
10.4 Estranes. Steroids in Which Ring a is Aromatic 164
10.4.1 Oestrogens. Oestrone. Estradiol 164
10.5 17?-Ethinyl Oestradiol 168
10.6 Early Pharmaceutical Production of Oestrogens 171
10.6.1 Progynon B Oleosum 172
10.7 Androstanes 173
10.7.1 Androgens. Androsterone. Testosterone 173
10.7.1.1 Androsterone 173
10.7.2 Testosterone 175
A Appendix to Chapter 10 179
A.1 Urinary Hormones in Medieval China 179
References 180
Further Reading 180
11 Early Steroid Chemistry. Sexual Hormones II, Progestagens. Pregnanes 181
11.1 Progesterone. The Hormone of Pregnancy, the Corpus Luteum Hormone 181
11.2 Progesterone as a Drug. Isolation of Progesterone 181
11.2.1 Progesterone: Isolation and Structural Determination 181
11.2.2 Approaches to the Synthesis of Progesterone in Germany Before WorldWar II 183
11.2.3 Progesterone as an Active Ingredient in Gestagen Formulations 185
11.2.4 Gestagens by the Oral Route: Ethistherone, the First Step 186
11.2.5 Progesterone as Prototype of Ovulation-Inhibiting Drugs: Synthetic Progesterone Analogues: Progestins 188
11.2.6 17?-hydroxyprogesterone 188
Further Reading 191
12 Steroid Chemistry III. Steroid Starting Materials 193
12.1 Phytochemicals as Raw Materials for the Semisynthesis of Steroidal Hormones 193
12.2 Mexican 'Dioscoreas', a Major Source of Steroids 194
12.2.1 From Saponin Diosgenin to Progesterone 194
12.2.1.1 Mexican Dioscoreas and Russell E. Marker 194
12.3 Rhizome of Mexican Dioscoreas as a Source of Steroids 198
12.4 Other Dioscoreas 201
12.5 Soya-bean Oil. A Major Source of Raw Materials for the Semisynthesis of Steroid Molecules 201
12.5.1 The Phytosterol Route: From Stigmasterol to Progesterone 201
12.5.2 Stigmasterol 202
12.5.3 Physostigmine, Stigmasterol and Percy Julian 202
12.6 Stigmasterol from Crude Soya Bean 203
12.7 Progesterone from Stigmasterol. Upjohn Process (1950s-1960s) 204
12.8 Soya-bean Seed 209
References 210
Further Reading 210
13 Steroid Chemistry IV. From Oestrone to 19-Nor Steroids 211
13.1 Contraceptive Agents 211
13.1.1 19-Nor Steroids 211
13.2 Norandrostane-based Steroids. Ethisterone 211
13.2.1 Industrial Production of Oestrone by Syntex. Production of Oestrone from Diosgenin 216
13.3 Androgenic-Anabolic Agents 219
13.3.1 Gonane-based Androgens 219
A Appendix to Chapter 13 221
A.1 19-Norsteroids 221
A.1.1 Total Synthesis 221
References 223
Further Reading 223
14 Steroid Chemistry V. Corticosteroids and Analogues. Adrenal Cortical Hormones 225
14.1 Cortisone, the Glucocorticoid Hormone. The Beginnings of the Cortisone Era 225
14.1.1 Cortisone from Bile Acids 227
14.2 Cortisone from Steroidal Sapogenins 229
14.2.1 Sarmentogenin 229
14.2.2 Hecogenin 230
14.2.3 Hecogenin from Sisal 230
14.3 Cortisone from Progesterone (1955). The Commercial Synthesis of Cortisone 232
14.3.1 17?-acetoxy Progesterone 237
14.3.2 Cortexolone Diacetate 238
14.4 Adrenal Cortical Hormones 239
14.4.1 Aldosterone, the Mineralocorticoid Hormone 239
14.5 Fluoro-Corticosteroids/Unsaturation Ring A 245
14.5.1 Fluorocorticoids: Fluodrocortisone 246
14.5.2 Methodology for Introducing Fluorine in 9? 247
14.6 Unsaturation Ring A. Prednisone, Prednisolone 248
14.7 6?-Methyl Corticosteroids 249
14.7.1 Introduction of 6? Methyl Group. 6?-Methylprednisolone 249
14.7.2 Triamcinolone 250
14.8 C-16 Methylcorticosteroids 252
14.8.1 Topical Corticosteroids 253
14.9 Corticosteroids. An Approach to an End... 256
14.10 Summary 257
References 260
Further Reading 260
15 Cardioactive Glycosides 261
15.1 Cardioactive Glycosides 261
15.1.1 Digitalis and Strophantus Glycosides 261
15.2 Introduction 261
15.2.1 Congestive Heart Failure (CHF) 264
15.3 Digitalis: Chemistry and Pharmacy 266
15.3.1 The Legal Reaction 268
15.3.2 Glycosides from Digitalis lanata 271
15.4 Glycosides from Digitalis Purpurea 271
15.5 Saponins on Digitalis Leaves 273
15.6 Strophantus 274
15.6.1 Convallaria 277
15.7 Squill (White Squill) 277
15.8 Toad Venom and Bufotoxin 279
Further Reading 280
Part V Alkaloids 281
16 Aminoalkaloids. Mescal. Ephedra 283
16.1 Drugs Affecting Adrenergic (Sympathetic) Neurotransmission 283
16.1.1 Ephedrine and Adrenergic Agents 283
16.2 Mescal. Mescaline 283
16.3 Ephedra. Drugs Affecting Adrenergic (Sympathetic) Neurotransmission. Adrenergic (Sympathomimetic) Agents 284
16.3.1 Ephedrine, Adrenaline (Epinephrine) and Related Drugs 284
16.4 'Ephedra' Alkaloids and Ephedrine 286
16.4.1 Ephedra. A Brief History 288
16.5 Ephedrine versus Epinephrine (Adrenaline) 289
16.6 Adrenaline (Epinephrine) and Related Drugs. Adrenergic Agents 290
16.6.1 Adrenergic Receptors 292
16.7 Epinephrine (Adrenaline) and Ephedrine Analogues. Structure-activity Relationships 293
16.8 Short Acting ?2 Adrenoreceptor Agonists (SABAs) 295
16.8.1 Selective ?2 Adrenergic Agonists: Pure Bronchodilators 295
16.9 Long Acting Selective ?2 Adrenoceptor Agonists (LABAs) 296
References 299
A Appendix to Chapter 16 299
A.1 Photos of Ephedra Bundles, Chart Ephedrine and Ephetonin from Merck KGaA (Darmstadt) Germany 299
17 Pyridine and Piperidine Alkaloids. Areca. Capsicum 303
17.1 Arecoline and Cholinergic Agents 303
17.2 Piperine 303
17.3 Capsaicin 305
17.4 Tropolone Alkaloids. Colchicumcapsaicin 306
17.5 Colchicine 307
References 309
A Appendix to Chapter 17 310
A.1 Acetylcholine and Cholinergic Receptors 310
18 Tropane Alkaloids I. Atropa belladonna and Datura stramonium 313
18.1 Tropane Alkaloids and Anticholinergic Drugs. Bronchodilators in Asthma and COPD 313
18.1.1 Reaction of Vitali-Morin 313
18.2 Atropine Atropine as Prototype of Anticholinergic Drugs 313
18.3 Scopolamine 319
18.3.1 Production of Alkaloids 320
18.4 Tropanol Esters. Atropine as a Prototype for the Development of Anticholinergic Drugs 322
18.4.1 Mydriatics Homatropine and Tropicamide 322
18.4.2 Antispasmodic Hioscine, Butyl Bromide 323
18.4.3 Short Acting Muscarinic Antagonists (SAMAs) 324
18.4.3.1 Synthetic Anticholinergics in Asthma and COPD 324
18.4.3.2 Long-Acting Muscarinic Antagonists (LAMAs) 325
18.5 Bronchodilators in the Treatment of Asthma and COPD (see also Chapter 16, Ephedra and Adrenergic Agents) 326
18.5.1 Dual Bronchodilator Therapy 327
18.6 Asthma/Allergic Disorders. COPD 328
References 328
19 Tropane Alkaloids II Coca Leaf (Cocae folium). Cocaine and Local Anaesthetics 331
19.1 Introduction. Historical Background 331
19.2 The Chemistry of Coca Leaves 335
19.2.1 Cocaine Hydrochloride. Cocaine an Ancient Anaesthetic 338
19.3 Synthetic Local Anaesthetics 338
19.3.1 Structural Variations on Cocaine. From Cocaine to Procaine. Amino-alcohol-type Local Anaesthetics 339
19.3.1.1 Eucaines, the First 339
19.3.2 Ortoforms, Stovaine, Benzocaine and Procaine 341
19.3.3 Anilide-type Local Anaesthetics. Lidocaine and Further Developments 342
19.3.3.1 Lidocaine 342
19.3.4 Mepivacaine, Bupivacaine, Ropivacaine 346
References 348
Further Reading 348
A Appendix to Chapter 19 348
A.1 Amide-Type Local Anaesthetics as Antiarryhtmic Drugs. Other Antiarrhythmic Drugs 348
20 Isoquinoline AlkaloidsIsoquinoline Alkaloids 351
20.1 Opium, Opium Alkaloids and Their Derivatives. Morphine. Structural Variations on Morphine 351
20.1.1 Introduction 351
20.1.2 Chemical Synthesis of Isoquinolines 351
20.1.2.1 Synthesis of Bischler-Napieralski 351
20.1.2.2 Synthesis of Pictet-Spengler 352
20.2 Opium, Opium Alkaloids and Their Derivatives 354
20.3 Opium 354
20.3.1 Divinum opus est sedare dolorem Hippocrates 354
20.3.2 Papaverine 357
20.3.3 Opium in the European Pharmacopoeia 359
20.3.4 Morphine 360
20.3.5 Codeine 361
20.3.6 Thebaine 361
20.4 Structural Variations on Morphine. Morphine Fragmentation 365
20.5 Structural Variations on Morphine I. Simple Modifications 365
20.5.1 Narcotic Antagonists 365
20.6 Structural Variations on Morphine II 367
20.6.1 Rigid Opioids: Morphinans and Benzomorphans 367
20.6.1.1 Morphinans 367
20.6.1.2 Benzomorphans 368
20.7 Structural Variations on Morphine III. Flexible Opioids 370
20.7.1 4-Phenyl Piperidines. Meperidine = Pethidine 370
20.7.2 Schaumann's Postulate 371
20.8 Structural Variations on Morphine IV. 4-Phenyl Piperidines 372
20.8.1 From Meperidine to Butyrophenone Neuroleptics 372
20.8.1.1 Haloperidol 372
20.9 Structural Variations on Morphine V. 4-Phenyl Piperidines 374
20.9.1 Opioid-Based Antidiarrheals. Diphenoxilate. Loperamide 374
20.10 Structural Variations on Morphine VI. Flexible Opioids 376
20.10.1 4-Anilido-Piperidines 376
20.10.1.1 Fentanyls 376
20.11 Structural Variations on Morphine VII 378
20.11.1 Methadone 378
20.12 Structural Variations on Morphine VIII. Simplified Codeines. Flexible Opioids as Dual Acting Agents: Tramadol and Tapentadol 378
20.12.1 Tapentadol 380
References 382
Further Reading 382
21 Isoquinoline Alkaloids 383
21.1 Introduction and Historical Background 383
21.1.1 Natural Curares 385
21.1.1.1 Historical Background 385
21.1.2 Early Missionaries and Explorers 387
21.1.2.1 Father Jose Acosta S.J. 387
21.1.2.2 Father Jose Gumilla S.J. 387
21.1.3 Alexander von Humboldt and Aime Bonpland 389
21.2 Eduard Friedrich Poeppig and Schomburgk brothers 390
21.2.1 Eduard Friedrich Poeppig 390
21.2.2 Schomburgk brothers, Robert and Moritz-Richard, German-born explorers and botanists 392
21.3 The First Experimental Studies 393
21.3.1 Early Classification of Curares 393
21.3.1.1 Claude Bernard 393
21.3.1.2 Rudolf Boehm 394
21.3.1.3 Tubocurare 394
21.3.1.4 Calabash Curare 394
21.4 Botanical Sources of Curares 396
21.5 Chemistry of Curares 396
21.5.1 Curare from Chondodendron. Intocostrin (R), the First Pharmaceutical Formulation of a Curare Extract 396
21.5.2 Tubocurarine, the First Curare-Like Drug 398
21.5.3 Curares. Several Methods of Preparation 400
21.6 Tetrahydroisoquinoline-based Curare-like Agents. From Alkaloid Petaline to Synthetic Atracurium 403
21.7 Steroid-based Curare-like Agents. From Alkaloid Malouetine to Pancuronium and Other Curoniums 408
21.8 Reversal Agents of Neuromuscular Blockade: Cyclodextrins: Sugammadex Sodium 414
References 415
21 bis-Terpenoid Isoquinoline Alkaloids: Ipeca Alkaloids 417
21.1 Alkaloids from Ipeca 417
22 Amaryllidacea Alkaloids. Galantamine 419
22.1 Galantamine 419
22.2 Racemic Synthesis of Galantamine 423
22.2.1 Asymmetric Synthesis of (?) Galantamine 425
References 425
Further Reading 425
23 Indole Alkaloids. Introduction 427
23.1 Physostigmine 427
23.2 Alzheimer's Disease 430
References 432
24 Terpene Indole Alkaloids. Introduction 433
24.1 Terpene Indole Alkaloids. Antitumour Vinca Alkaloids 433
24.1.1 Vinorelbine 433
24.2 Terpene Indole Alkaloids. Reserpine 434
24.2.1 Vinorelbine 438
24.3 Reserpine 439
24.4 Terpene-Indole Alkaloids. Ergot Alkaloids. Ergotamine. Ergobasine 440
24.4.1 Ergolines 444
References 445
Further Reading 445
A Appendix to Chapter 24 445
A.1 Triptans 445
25 Quinoline Alkaloids 447
25.1 Malaria. Cinchona Bark and Quinine 447
25.1.1 From Quinine to Synthetic Antimalarials 447
25.1.2 The Plasmodium Cycle 447
25.2 Cinchona Bark 449
25.2.1 Introduction and Historical Background 449
25.3 Scientific Expeditions to the NewWorld. The Spanish Enlightenment (Eighteenth Century) 451
25.4 Cinchona Bark Alkaloids. The Chemistry of Cinchona Alkaloids. An Approach 457
25.4.1 Isolation and Production of Quinine 457
25.4.2 The Quinine Structure 459
25.4.3 Synthesis deWooward-Doering 460
25.4.4 Quinine Sulphate, Today 463
25.4.5 Quinidine Sulphate 463
25.5 From Quinine to Synthetic Antimalarials 463
25.5.1 Amino-Acridines and Amino-Quinolines 463
25.5.2 Chloroquine, Antimalarial Discovered Twice 464
References and Notes 467
A Appendix to Chapter 25 468
A.1 Synthetic Antimalarials. Antifolates 468
A.1.1 Proguanil/Cycloguanil 468
A.1.2 Atovaquone 469
26 Quinoline Alkaloids 471
26.1 Camptotheca 471
26.1.1 Camptothecine and Derivatives as Anticancer Agents 471
References 477
Further Reading 478
27 Miscellaneous 479
27.1 Cephalotaxus Alkaloids: Homoharringtonine (Omacetaxine Mepesuccinate) 479
27.2 Purine Alkaloids: Xanthines 482
References 484
Index 485
Preface xxi
Introduction & Historical Background xxxi
Part I Carbohydrates and Natural Products related to Carbohydrates 1
1 Carbohydrates 3
1.1 Polisaccarides 3
1.1.1 Gums and Mucilages 3
1.1.2 Mucilages 6
1.2 Carbohydrates as Antidiabetic Agents 6
1.2.1 ?-Glucosidase Inhibitors in Diabetes 6
A Appendix to Chapter 1 7
A.1 Non-Carbohydrates as Antidiabetic Agents 7
A.2 Type-II Antidiabetic Agents 9
A.3 Biguanides 12
2 Natural Products Related to Carbohydrates 15
2.1 Glycosides 15
2.1.1 Introduction 15
2.2 Anthraquinone Glycoside as Laxatives 16
2.3 Phenol Glycosides 19
2.3.1 Phlorizin 19
2.4 Novel Strategy in the Treatment of Type-2 Diabetes 21
2.4.1 Glycoside Type-II Antidiabetic Agents 21
2.4.2 Gliflozins 21
2.4.3 Gliflozins and Their Cardiovascular Benefits 23
References 24
Part II Polyphenols and Related Derivatives 27
3 Polyphenols and Related Derivatives 29
3.1 Introduction 29
3.1.1 Polyphenols 29
3.2 The Biosynthetic Shikimate Pathway 30
3.2.1 Aromatic Aminoacids 30
3.2.1.1 Phenyl Propanoids 30
3.2.1.2 Gallic Acid and Tannins 30
3.2.1.3 Galls 32
3.3 Phenylpropanes 33
3.3.1 Cinnamic Acid 33
3.3.2 Balsams 34
3.3.3 Cinnamon 36
3.3.4 Essential (Volatile) Oils 36
3.3.5 Vanilla 38
3.3.6 Vanillin 40
3.4 Podophyllotoxin 41
References 44
Further Reading 44
4 Benzopyrane-Based Structures 45
4.1 Coumarins, Furochromones 45
4.2 Coumarins 45
4.2.1 Anticoagulants from Sweet Clover 45
4.3 From Plant-Derived Coumarins to Modern Non Plant-Derived 47
4.3.1 Anticoagulant Therapeutic Agents 47
4.4 Furochromones 52
4.4.1 Khellin as a Source of Coronary Dilators: Calcium Channel Blockers and Other Related Derivatives 52
4.5 BIS-Chromones as Mast Cell Stabilizers 59
4.5.1 Disodium cromoglicate. Chromolyn sodium as bronchodilator 59
4.5.2 Benzofuran Antiarrythmia 60
References 61
5 Flavonoids 63
5.1 Flavones 63
5.2 Rutin (Rutoside) 68
5.3 Quercetin 70
5.4 Tea 71
5.5 Isoflavones 72
5.6 Flavone Alkaloids and Indol-based Natural Products as Cyclic-dependent Kinase Inhibitors (CDK-Inhibitors) 74
5.6.1 Flavone Alkaloid Rohituquine, Flavopiridol and Pyrimidine-related CDK Inhibitors 74
5.6.1.1 The Cell Division Cycle 74
5.6.2 Development of CDK Inhibitors 76
5.6.2.1 Non-Plant Derived CDK Inhibitors 78
5.7 Indole-based Natural Products as Cyclic Dependent Kinase Inhibitors 83
5.7.1 Indigo and Indirubine CDK Inhibitors 83
References 88
Part III Terpenes and Isoprenoids 91
6 Terpenes and Isoprenoids 93
6.1 Terpenes 93
6.1.1 Introduction 93
6.2 Monoterpenes 95
6.3 Cannabis and cannabinoids 95
6.3.1 Cannabis 95
6.3.1.1 The Long Journey of a Controversial and Paradigmatic Plant 95
6.3.2 Cultivation 97
6.3.3 Chemistry 98
6.3.4 Terpenes in Cannabis 100
6.3.5 Cannabis as a Crude Drug 101
6.3.6 Therapeutic Cannabinoids 102
6.3.7 Cannabidiol 103
6.3.8 Endocannabinoids 105
References 107
Further Reading 108
7 Sexquiterpenes (C15) and Diterpenes (C20) 109
7.1 Sexquiterpenes: Artemisia 109
7.1.1 Diterpenes: Ginkgo 109
7.2 Santonine 109
7.3 Artemisinin 110
7.3.1 From Ancient Recipes to Modern Drugs 112
7.3.1.1 Artemisinin Production 114
7.4 Diterpenes 117
7.4.1 Ginkgolides 117
References 122
8 Diterpenes II. Taxanes 125
8.1 Taxanes: Paclitaxel, Docetaxel, Cabazitaxel 125
8.1.1 Semi-Synthesis of Taxanes 128
8.1.2 Production 130
References 133
Further Reading 133
9 Triterpenes 135
9.1 Triterpenes (C30) 135
9.2 Glycoside Pentacyclic Triterpenoid Saponines 135
9.2.1 Triterpenoid Saponin Biosynthesis 137
9.2.2 Glycyrrhizin and Glycyrrhizic Acid 139
9.2.2.1 Liquorice Root 139
9.2.3 Quillaja Saponin 141
9.3 Ginseng and Ginsenosides 142
9.3.1 Ginsenoside Biosynthesis 144
9.4 Siberiang Ginseng (Eleutherococcus) 146
9.5 Triterpene Carboxylic Acids 146
9.5.1 Betulinic Acid 147
References 148
Further Reading 149
Part IV Steroids and Plant Natural products as raw materials for Steroid production. Cardioactive Glycosides 151
10 Early Steroid Chemistry. Introduction. Sexual Hormones I 153
10.1 Steroids 153
10.1.1 Introduction 153
10.1.1.1 A brief history 153
10.1.2 Five Centuries Later... 155
10.2 Nomenclature/Structural Determination/ Stereochemistry 161
10.3 Structural Determination 162
10.3.1 Primitive Methods 162
10.4 Estranes. Steroids in Which Ring a is Aromatic 164
10.4.1 Oestrogens. Oestrone. Estradiol 164
10.5 17?-Ethinyl Oestradiol 168
10.6 Early Pharmaceutical Production of Oestrogens 171
10.6.1 Progynon B Oleosum 172
10.7 Androstanes 173
10.7.1 Androgens. Androsterone. Testosterone 173
10.7.1.1 Androsterone 173
10.7.2 Testosterone 175
A Appendix to Chapter 10 179
A.1 Urinary Hormones in Medieval China 179
References 180
Further Reading 180
11 Early Steroid Chemistry. Sexual Hormones II, Progestagens. Pregnanes 181
11.1 Progesterone. The Hormone of Pregnancy, the Corpus Luteum Hormone 181
11.2 Progesterone as a Drug. Isolation of Progesterone 181
11.2.1 Progesterone: Isolation and Structural Determination 181
11.2.2 Approaches to the Synthesis of Progesterone in Germany Before WorldWar II 183
11.2.3 Progesterone as an Active Ingredient in Gestagen Formulations 185
11.2.4 Gestagens by the Oral Route: Ethistherone, the First Step 186
11.2.5 Progesterone as Prototype of Ovulation-Inhibiting Drugs: Synthetic Progesterone Analogues: Progestins 188
11.2.6 17?-hydroxyprogesterone 188
Further Reading 191
12 Steroid Chemistry III. Steroid Starting Materials 193
12.1 Phytochemicals as Raw Materials for the Semisynthesis of Steroidal Hormones 193
12.2 Mexican 'Dioscoreas', a Major Source of Steroids 194
12.2.1 From Saponin Diosgenin to Progesterone 194
12.2.1.1 Mexican Dioscoreas and Russell E. Marker 194
12.3 Rhizome of Mexican Dioscoreas as a Source of Steroids 198
12.4 Other Dioscoreas 201
12.5 Soya-bean Oil. A Major Source of Raw Materials for the Semisynthesis of Steroid Molecules 201
12.5.1 The Phytosterol Route: From Stigmasterol to Progesterone 201
12.5.2 Stigmasterol 202
12.5.3 Physostigmine, Stigmasterol and Percy Julian 202
12.6 Stigmasterol from Crude Soya Bean 203
12.7 Progesterone from Stigmasterol. Upjohn Process (1950s-1960s) 204
12.8 Soya-bean Seed 209
References 210
Further Reading 210
13 Steroid Chemistry IV. From Oestrone to 19-Nor Steroids 211
13.1 Contraceptive Agents 211
13.1.1 19-Nor Steroids 211
13.2 Norandrostane-based Steroids. Ethisterone 211
13.2.1 Industrial Production of Oestrone by Syntex. Production of Oestrone from Diosgenin 216
13.3 Androgenic-Anabolic Agents 219
13.3.1 Gonane-based Androgens 219
A Appendix to Chapter 13 221
A.1 19-Norsteroids 221
A.1.1 Total Synthesis 221
References 223
Further Reading 223
14 Steroid Chemistry V. Corticosteroids and Analogues. Adrenal Cortical Hormones 225
14.1 Cortisone, the Glucocorticoid Hormone. The Beginnings of the Cortisone Era 225
14.1.1 Cortisone from Bile Acids 227
14.2 Cortisone from Steroidal Sapogenins 229
14.2.1 Sarmentogenin 229
14.2.2 Hecogenin 230
14.2.3 Hecogenin from Sisal 230
14.3 Cortisone from Progesterone (1955). The Commercial Synthesis of Cortisone 232
14.3.1 17?-acetoxy Progesterone 237
14.3.2 Cortexolone Diacetate 238
14.4 Adrenal Cortical Hormones 239
14.4.1 Aldosterone, the Mineralocorticoid Hormone 239
14.5 Fluoro-Corticosteroids/Unsaturation Ring A 245
14.5.1 Fluorocorticoids: Fluodrocortisone 246
14.5.2 Methodology for Introducing Fluorine in 9? 247
14.6 Unsaturation Ring A. Prednisone, Prednisolone 248
14.7 6?-Methyl Corticosteroids 249
14.7.1 Introduction of 6? Methyl Group. 6?-Methylprednisolone 249
14.7.2 Triamcinolone 250
14.8 C-16 Methylcorticosteroids 252
14.8.1 Topical Corticosteroids 253
14.9 Corticosteroids. An Approach to an End... 256
14.10 Summary 257
References 260
Further Reading 260
15 Cardioactive Glycosides 261
15.1 Cardioactive Glycosides 261
15.1.1 Digitalis and Strophantus Glycosides 261
15.2 Introduction 261
15.2.1 Congestive Heart Failure (CHF) 264
15.3 Digitalis: Chemistry and Pharmacy 266
15.3.1 The Legal Reaction 268
15.3.2 Glycosides from Digitalis lanata 271
15.4 Glycosides from Digitalis Purpurea 271
15.5 Saponins on Digitalis Leaves 273
15.6 Strophantus 274
15.6.1 Convallaria 277
15.7 Squill (White Squill) 277
15.8 Toad Venom and Bufotoxin 279
Further Reading 280
Part V Alkaloids 281
16 Aminoalkaloids. Mescal. Ephedra 283
16.1 Drugs Affecting Adrenergic (Sympathetic) Neurotransmission 283
16.1.1 Ephedrine and Adrenergic Agents 283
16.2 Mescal. Mescaline 283
16.3 Ephedra. Drugs Affecting Adrenergic (Sympathetic) Neurotransmission. Adrenergic (Sympathomimetic) Agents 284
16.3.1 Ephedrine, Adrenaline (Epinephrine) and Related Drugs 284
16.4 'Ephedra' Alkaloids and Ephedrine 286
16.4.1 Ephedra. A Brief History 288
16.5 Ephedrine versus Epinephrine (Adrenaline) 289
16.6 Adrenaline (Epinephrine) and Related Drugs. Adrenergic Agents 290
16.6.1 Adrenergic Receptors 292
16.7 Epinephrine (Adrenaline) and Ephedrine Analogues. Structure-activity Relationships 293
16.8 Short Acting ?2 Adrenoreceptor Agonists (SABAs) 295
16.8.1 Selective ?2 Adrenergic Agonists: Pure Bronchodilators 295
16.9 Long Acting Selective ?2 Adrenoceptor Agonists (LABAs) 296
References 299
A Appendix to Chapter 16 299
A.1 Photos of Ephedra Bundles, Chart Ephedrine and Ephetonin from Merck KGaA (Darmstadt) Germany 299
17 Pyridine and Piperidine Alkaloids. Areca. Capsicum 303
17.1 Arecoline and Cholinergic Agents 303
17.2 Piperine 303
17.3 Capsaicin 305
17.4 Tropolone Alkaloids. Colchicumcapsaicin 306
17.5 Colchicine 307
References 309
A Appendix to Chapter 17 310
A.1 Acetylcholine and Cholinergic Receptors 310
18 Tropane Alkaloids I. Atropa belladonna and Datura stramonium 313
18.1 Tropane Alkaloids and Anticholinergic Drugs. Bronchodilators in Asthma and COPD 313
18.1.1 Reaction of Vitali-Morin 313
18.2 Atropine Atropine as Prototype of Anticholinergic Drugs 313
18.3 Scopolamine 319
18.3.1 Production of Alkaloids 320
18.4 Tropanol Esters. Atropine as a Prototype for the Development of Anticholinergic Drugs 322
18.4.1 Mydriatics Homatropine and Tropicamide 322
18.4.2 Antispasmodic Hioscine, Butyl Bromide 323
18.4.3 Short Acting Muscarinic Antagonists (SAMAs) 324
18.4.3.1 Synthetic Anticholinergics in Asthma and COPD 324
18.4.3.2 Long-Acting Muscarinic Antagonists (LAMAs) 325
18.5 Bronchodilators in the Treatment of Asthma and COPD (see also Chapter 16, Ephedra and Adrenergic Agents) 326
18.5.1 Dual Bronchodilator Therapy 327
18.6 Asthma/Allergic Disorders. COPD 328
References 328
19 Tropane Alkaloids II Coca Leaf (Cocae folium). Cocaine and Local Anaesthetics 331
19.1 Introduction. Historical Background 331
19.2 The Chemistry of Coca Leaves 335
19.2.1 Cocaine Hydrochloride. Cocaine an Ancient Anaesthetic 338
19.3 Synthetic Local Anaesthetics 338
19.3.1 Structural Variations on Cocaine. From Cocaine to Procaine. Amino-alcohol-type Local Anaesthetics 339
19.3.1.1 Eucaines, the First 339
19.3.2 Ortoforms, Stovaine, Benzocaine and Procaine 341
19.3.3 Anilide-type Local Anaesthetics. Lidocaine and Further Developments 342
19.3.3.1 Lidocaine 342
19.3.4 Mepivacaine, Bupivacaine, Ropivacaine 346
References 348
Further Reading 348
A Appendix to Chapter 19 348
A.1 Amide-Type Local Anaesthetics as Antiarryhtmic Drugs. Other Antiarrhythmic Drugs 348
20 Isoquinoline AlkaloidsIsoquinoline Alkaloids 351
20.1 Opium, Opium Alkaloids and Their Derivatives. Morphine. Structural Variations on Morphine 351
20.1.1 Introduction 351
20.1.2 Chemical Synthesis of Isoquinolines 351
20.1.2.1 Synthesis of Bischler-Napieralski 351
20.1.2.2 Synthesis of Pictet-Spengler 352
20.2 Opium, Opium Alkaloids and Their Derivatives 354
20.3 Opium 354
20.3.1 Divinum opus est sedare dolorem Hippocrates 354
20.3.2 Papaverine 357
20.3.3 Opium in the European Pharmacopoeia 359
20.3.4 Morphine 360
20.3.5 Codeine 361
20.3.6 Thebaine 361
20.4 Structural Variations on Morphine. Morphine Fragmentation 365
20.5 Structural Variations on Morphine I. Simple Modifications 365
20.5.1 Narcotic Antagonists 365
20.6 Structural Variations on Morphine II 367
20.6.1 Rigid Opioids: Morphinans and Benzomorphans 367
20.6.1.1 Morphinans 367
20.6.1.2 Benzomorphans 368
20.7 Structural Variations on Morphine III. Flexible Opioids 370
20.7.1 4-Phenyl Piperidines. Meperidine = Pethidine 370
20.7.2 Schaumann's Postulate 371
20.8 Structural Variations on Morphine IV. 4-Phenyl Piperidines 372
20.8.1 From Meperidine to Butyrophenone Neuroleptics 372
20.8.1.1 Haloperidol 372
20.9 Structural Variations on Morphine V. 4-Phenyl Piperidines 374
20.9.1 Opioid-Based Antidiarrheals. Diphenoxilate. Loperamide 374
20.10 Structural Variations on Morphine VI. Flexible Opioids 376
20.10.1 4-Anilido-Piperidines 376
20.10.1.1 Fentanyls 376
20.11 Structural Variations on Morphine VII 378
20.11.1 Methadone 378
20.12 Structural Variations on Morphine VIII. Simplified Codeines. Flexible Opioids as Dual Acting Agents: Tramadol and Tapentadol 378
20.12.1 Tapentadol 380
References 382
Further Reading 382
21 Isoquinoline Alkaloids 383
21.1 Introduction and Historical Background 383
21.1.1 Natural Curares 385
21.1.1.1 Historical Background 385
21.1.2 Early Missionaries and Explorers 387
21.1.2.1 Father Jose Acosta S.J. 387
21.1.2.2 Father Jose Gumilla S.J. 387
21.1.3 Alexander von Humboldt and Aime Bonpland 389
21.2 Eduard Friedrich Poeppig and Schomburgk brothers 390
21.2.1 Eduard Friedrich Poeppig 390
21.2.2 Schomburgk brothers, Robert and Moritz-Richard, German-born explorers and botanists 392
21.3 The First Experimental Studies 393
21.3.1 Early Classification of Curares 393
21.3.1.1 Claude Bernard 393
21.3.1.2 Rudolf Boehm 394
21.3.1.3 Tubocurare 394
21.3.1.4 Calabash Curare 394
21.4 Botanical Sources of Curares 396
21.5 Chemistry of Curares 396
21.5.1 Curare from Chondodendron. Intocostrin (R), the First Pharmaceutical Formulation of a Curare Extract 396
21.5.2 Tubocurarine, the First Curare-Like Drug 398
21.5.3 Curares. Several Methods of Preparation 400
21.6 Tetrahydroisoquinoline-based Curare-like Agents. From Alkaloid Petaline to Synthetic Atracurium 403
21.7 Steroid-based Curare-like Agents. From Alkaloid Malouetine to Pancuronium and Other Curoniums 408
21.8 Reversal Agents of Neuromuscular Blockade: Cyclodextrins: Sugammadex Sodium 414
References 415
21 bis-Terpenoid Isoquinoline Alkaloids: Ipeca Alkaloids 417
21.1 Alkaloids from Ipeca 417
22 Amaryllidacea Alkaloids. Galantamine 419
22.1 Galantamine 419
22.2 Racemic Synthesis of Galantamine 423
22.2.1 Asymmetric Synthesis of (?) Galantamine 425
References 425
Further Reading 425
23 Indole Alkaloids. Introduction 427
23.1 Physostigmine 427
23.2 Alzheimer's Disease 430
References 432
24 Terpene Indole Alkaloids. Introduction 433
24.1 Terpene Indole Alkaloids. Antitumour Vinca Alkaloids 433
24.1.1 Vinorelbine 433
24.2 Terpene Indole Alkaloids. Reserpine 434
24.2.1 Vinorelbine 438
24.3 Reserpine 439
24.4 Terpene-Indole Alkaloids. Ergot Alkaloids. Ergotamine. Ergobasine 440
24.4.1 Ergolines 444
References 445
Further Reading 445
A Appendix to Chapter 24 445
A.1 Triptans 445
25 Quinoline Alkaloids 447
25.1 Malaria. Cinchona Bark and Quinine 447
25.1.1 From Quinine to Synthetic Antimalarials 447
25.1.2 The Plasmodium Cycle 447
25.2 Cinchona Bark 449
25.2.1 Introduction and Historical Background 449
25.3 Scientific Expeditions to the NewWorld. The Spanish Enlightenment (Eighteenth Century) 451
25.4 Cinchona Bark Alkaloids. The Chemistry of Cinchona Alkaloids. An Approach 457
25.4.1 Isolation and Production of Quinine 457
25.4.2 The Quinine Structure 459
25.4.3 Synthesis deWooward-Doering 460
25.4.4 Quinine Sulphate, Today 463
25.4.5 Quinidine Sulphate 463
25.5 From Quinine to Synthetic Antimalarials 463
25.5.1 Amino-Acridines and Amino-Quinolines 463
25.5.2 Chloroquine, Antimalarial Discovered Twice 464
References and Notes 467
A Appendix to Chapter 25 468
A.1 Synthetic Antimalarials. Antifolates 468
A.1.1 Proguanil/Cycloguanil 468
A.1.2 Atovaquone 469
26 Quinoline Alkaloids 471
26.1 Camptotheca 471
26.1.1 Camptothecine and Derivatives as Anticancer Agents 471
References 477
Further Reading 478
27 Miscellaneous 479
27.1 Cephalotaxus Alkaloids: Homoharringtonine (Omacetaxine Mepesuccinate) 479
27.2 Purine Alkaloids: Xanthines 482
References 484
Index 485
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