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
1.2 Carbohydrates as Antidiabetic Agents 6

2 Natural Products Related to Carbohydrates 15
2.1 Glycosides 15
2.2 Anthraquinone Glycoside as Laxatives 16
2.3 Phenol Glycosides 19
2.4 Novel Strategy in the Treatment of Type-2 Diabetes 21

Part II Polyphenols and Related Derivatives 27

3 Polyphenols and Related Derivatives 29
3.1 Introduction 29
3.2 The Biosynthetic Shikimate Pathway 30
3.3 Phenylpropanes 33
3.4 Podophyllotoxin 41

4 Benzopyrane-Based Structures 45

4.1 Coumarins, Furochromones 45
4.2 Coumarins 45
4.3 From Plant-Derived Coumarins to Modern Non Plant-Derived 47
4.4 Furochromones 52
4.5 BIS-Chromones as Mast Cell Stabilizers 59

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
5.7 Indole-based Natural Products as Cyclic Dependent Kinase Inhibitors 83

Part III Terpenes and Isoprenoids 91

6 Terpenes and Isoprenoids 93
6.1 Terpenes 93
6.2 Monoterpenes 95
6.3 Cannabis and cannabinoids 95

7 Sexquiterpenes (C15) and Diterpenes (C20) 109
7.1 Sexquiterpenes: Artemisia 109
7.2 Santonine 109
7.3 Artemisinin 110
7.4 Diterpenes 117

8 Diterpenes II. Taxanes 125
8.1 Taxanes: Paclitaxel, Docetaxel, Cabazitaxel 125

9 Triterpenes 135
9.1 Triterpenes (C30) 135
9.2 Glycoside Pentacyclic Triterpenoid Saponines 135
9.3 Ginseng and Ginsenosides 142
9.4 Siberiang Ginseng (Eleutherococcus) 146
9.5 Triterpene Carboxylic Acids 146

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
10.2 Nomenclature/Structural Determination/ Stereochemistry 161
10.3 Structural Determination 162
10.4 Estranes. Steroids in Which Ring a is Aromatic 164
10.5 17α-Ethinyl Oestradiol 168
10.6 Early Pharmaceutical Production of Oestrogens 171
10.7 Androstanes 173

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

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
12.3 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
12.6 Stigmasterol from Crude Soya Bean 203
12.7 Progesterone from Stigmasterol. Upjohn Process (1950s–1960s) 204
12.8 Soya-bean Seed 209

13 Steroid Chemistry IV. From Oestrone to 19-Nor Steroids 211
13.1 Contraceptive Agents 211
13.2 Norandrostane-based Steroids. Ethisterone 211
13.3 Androgenic-Anabolic Agents 219

14 Steroid Chemistry V. Corticosteroids and Analogues. Adrenal Cortical Hormones 225
14.1 Cortisone, the Glucocorticoid Hormone. The Beginnings of the Cortisone Era 225
14.2 Cortisone from Steroidal Sapogenins 229
14.3 Cortisone from Progesterone (1955). The Commercial Synthesis of Cortisone 232
14.4 Adrenal Cortical Hormones 239
14.5 Fluoro-Corticosteroids/Unsaturation Ring A 245
14.6 Unsaturation Ring A. Prednisone, Prednisolone 248
14.7 6α-Methyl Corticosteroids 249
14.8 C-16 Methylcorticosteroids 252
14.9 Corticosteroids. An Approach to an End... 256
14.10 Summary 257

15 Cardioactive Glycosides 261
15.1 Cardioactive Glycosides 261
15.2 Introduction 261
15.3 Digitalis: Chemistry and Pharmacy 266
15.4 Glycosides from Digitalis Purpurea 271
15.5 Saponins on Digitalis Leaves 273
15.6 Strophantus 274
15.7 Squill (White Squill) 277
15.8 Toad Venom and Bufotoxin 279

Part V Alkaloids 281

16 Aminoalkaloids. Mescal. Ephedra 283
16.1 Drugs Affecting Adrenergic (Sympathetic) Neurotransmission 283
16.2 Mescal. Mescaline 283
16.3 Ephedra. Drugs Affecting Adrenergic (Sympathetic) Neurotransmission. Adrenergic (Sympathomimetic) Agents 284
16.4 'Ephedra' Alkaloids and Ephedrine 286
16.5 Ephedrine versus Epinephrine (Adrenaline) 289
16.6 Adrenaline (Epinephrine) and Related Drugs. Adrenergic Agents 290
16.7 Epinephrine (Adrenaline) and Ephedrine Analogues. Structure-activity Relationships 293
16.8 Short Acting β2 Adrenoreceptor Agonists (SABAs) 295
16.9 Long Acting Selective β2 Adrenoceptor Agonists (LABAs) 296

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

18 Tropane Alkaloids I. Atropa belladonna and Datura stramonium 313
18.1 Tropane Alkaloids and Anticholinergic Drugs. Bronchodilators in Asthma and COPD 313
18.2 Atropine Atropine as Prototype of Anticholinergic Drugs 313
18.3 Scopolamine 319
18.4 Tropanol Esters. Atropine as a Prototype for the Development of Anticholinergic Drugs 322
18.5 Bronchodilators in the Treatment of Asthma and COPD (see also Chapter 16, Ephedra and Adrenergic Agents) 326
18.6 Asthma/Allergic Disorders. COPD 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
19.3 Synthetic Local Anaesthetics 338

20 Isoquinoline AlkaloidsIsoquinoline Alkaloids 351
20.1 Opium, Opium Alkaloids and Their Derivatives. Morphine. Structural Variations on Morphine 351
20.2 Opium, Opium Alkaloids and Their Derivatives 354
20.3 Opium 354
20.4 Structural Variations on Morphine. Morphine Fragmentation 365
20.5 Structural Variations on Morphine I. Simple Modifications 365
20.6 Structural Variations on Morphine II 367
20.7 Structural Variations on Morphine III. Flexible Opioids 370
20.8 Structural Variations on Morphine IV. 4-Phenyl Piperidines 372
20.9 Structural Variations on Morphine V. 4-Phenyl Piperidines 374
20.10 Structural Variations on Morphine VI. Flexible Opioids 376
20.11 Structural Variations on Morphine VII 378
20.12 Structural Variations on Morphine VIII. Simplified Codeines. Flexible Opioids as Dual Acting Agents: Tramadol and Tapentadol 378

21 Isoquinoline Alkaloids 383
21.1 Introduction and Historical Background 383
21.2 Eduard Friedrich Poeppig and Schomburgk brothers 390
21.3 The First Experimental Studies 393
21.4 Botanical Sources of Curares 396
21.5 Chemistry of Curares 396
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

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

23 Indole Alkaloids. Introduction 427
23.1 Physostigmine 427
23.2 Alzheimer's Disease 430

24 Terpene Indole Alkaloids. Introduction 433
24.1 Terpene Indole Alkaloids. Antitumour Vinca Alkaloids 433
24.2 Terpene Indole Alkaloids. Reserpine 434
24.3 Reserpine 439
24.4 Terpene-Indole Alkaloids. Ergot Alkaloids. Ergotamine. Ergobasine 440

25 Quinoline Alkaloids 447
25.1 Malaria. Cinchona Bark and Quinine 447
25.2 Cinchona Bark 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
25.5 From Quinine to Synthetic Antimalarials 463

26 Quinoline Alkaloids 471
26.1 Camptotheca 471

27 Miscellaneous 479
27.1 Cephalotaxus Alkaloids: Homoharringtonine (Omacetaxine Mepesuccinate) 479
27.2 Purine Alkaloids: Xanthines 482

References 484
Index 485