Traduzione di Nannai
original text
1 Ecological Roles of Alkaloids 3
Michael Wink
1.1
Introduction: Defense Strategies in Plants 3
1.2 Ecological Roles of Alkaloids 4
1.3 Modes of Action 9
1.3.1 Unspecific Interactions 11
1.3.2 Specific Interactions 12
1.3.3 Cytotoxicity of Alkaloids 16
1.4 Evolution of Alkaloidal Defense Systems 19
1.5 Conclusions 23
2 Antitumor Alkaloids in Clinical Use or in Clinical Trials 25
Muriel Cuendet, John M. Pezzuto
2.1 Introduction 25
2.2 Antitumor Alkaloids in Clinical Use 25
2.2.1 Vinca Alkaloids 25
2.2.1.1 Vinblastine (VLB, 1) 28
2.2.1.2 Vincristine (VCR, 2) 28
2.2.1.3 Vindesine (VDS, 3) 28
2.2.1.4 Vinorelbine (VRLB, 4) 29
2.2.1.5 Vinflunine (VFL, 5) 29
2.2.2 Camptothecin and Analogs 29
2.2.2.1 Camptothecin (CPT, 6) 31
2.2.2.2 Irinotecan (CPT-11) 31
2.2.2.3 Topotecan 32
2.2.2.4 Exatecan 32
2.2.2.5 Gimatecan 32
2.2.2.6 Karenitecin 32
2.2.2.7 Lurtotecan 32
2.2.2.8 Rubitecan (9-nitrocamptothecin) 33
2.2.3 Taxanes 33
2.2.3.1 Paclitaxel 33
2.2.3.2 Docetaxel 35
2.3 Antitumor Alkaloids in Clinical Trials 36
2.3.1 Ecteinascidin-743 (Yondelis, Trabectedin) 36
2.3.2 7-Hydroxystaurosporine (UCN-01) 37
2.3.3 Ellipticine and Analogs 37
2.3.4 Acronycine and Analogs 38
2.3.5 Colchicine and Analogs 39
2.3.6 Ukrain 40
2.4 Alkaloids Used for MDR Reversal 40
2.4.1 Cinchona Alkaloids 40
2.4.2 Dofequidar Fumarate (MS-209) 41
2.5 Alkaloids Used for Cancer Prevention 42
2.6 Conclusions 43
2.7 Acknowledgments 44
3 Alkaloids and the Bitter Taste 53
Angela Bassoli, Gigliola Borgonovo, Gilberto Busnelli
3.1 Introduction 53
3.2 The Bitter Taste Chemoreception Mechanism 54
3.3 Bitter Alkaloids in Food 58
3.4 The Bitter Taste of Alkaloids in Other Drugs and Poisons 63
3.5 Alkaloids and Taste in Insects 66
3.6 The Bitter Taste of Alkaloids: Should We Avoid, Mask, or
Understand? 69
3.7 Acknowledgments 70
4 Capsaicin and Capsaicinoids 73
Giovanni Appendino
4.1 Introduction 73
4.2 What Is an Alkaloid? Is Capsaicin an Alkaloid? 73
4.3 Diversity, Biosynthesis, and Metabolism of Capsaicinoids 77
4.4 Quantization of Capsaicinoids and Their Distribution in Chili
Pepper 83
4.5 Isolation and Synthesis of Capsaicin 86
4.6 TRV1 as the Biological Target of Capsaicin and the Ecological Raison
d’eˆtre of Capsaicinoids: A Molecular View 90
4.7 Naturally Occurring Analogs and Antagonists of Capsaicin
and Endogenous Vanilloids 93
4.8 Structure–Activity Relationships of Capsaicinoids 94
VI Contents
4.9 Molecular Gastronomy of Hot Food 98
4.9.1 Biomedical Relevance of Capsaicin-Induced Trigeminal
Responses 98
4.9.2 Effect of Capsaicin on Taste 98
4.9.3 Gustatory Sweating 99
4.9.4 Gustatory Rhinitis 99
4.9.5 Hot Food Mitridatism 99
4.9.6 Effect of Capsaicin on Digestion 100
4.9.7 Capsaicin and Stomach Cancer 100
4.9.8 The Effect of Age and Sex on the Sensitivity to Capsaicin 100
4.9.9 Capsaicin as a Slimming Agent 101
4.9.10 Quenching Capsaicin 101
4.9.11 Chilies and Olive Oil 102
4.9.12 Who Should Avoid Chilies? 102
4.9.13 How can the Pungency of Chilies be Moderated? 102
4.9.14 Psychology of Pepper Consumption 102
4.10 Conclusions 103
4.11 Acknowledgments 103
5 Glycosidase-Inhibiting Alkaloids: Isolation, Structure, and
Application 111
Naoki Asano
5.1 Introduction 111
5.2 Isolation and Structural Characterization 111
5.2.1 Deoxynojirimycin and Related Compounds 112
5.2.1.1 Isolation from Morus spp. (Moraceae) 112
5.2.1.2 Isolation from Thai Medicinal Plants ‘‘Thopthaep’’ and ‘‘Cha
Em Thai’’ 113
5.2.2 a-Homonojirimycin and Related Compounds 115
5.2.2.1 Isolation from Garden Plants 115
5.2.2.2 Isolation from the Thai Medicinal Plant ‘‘Non Tai Yak’’ 117
5.2.2.3 Isolation from Adenophora spp. (Campanulaceae) 117
5.2.3 Indolizidine and Pyrrolizidine Alkaloids 117
5.2.3.1 Isolation from the Leguminosae Family 118
5.2.3.2 Isolation from the Hyacinthaceae Family 120
5.2.4 Nortropane Alkaloids 122
5.2.4.1 Isolation from the Solanaceae Family 123
5.2.4.2 Isolation from the Convolvulaceae Family 124
5.3 Biological Activities and Therapeutic Application 125
5.3.1 Antidiabetic Agents 125
5.3.1.1 a-Glucosidase Inhibitors 125
5.3.1.2 Glycogen Phosphorylase Inhibitors 128
5.3.1.3 Herbal Medicines 128
5.3.2 Molecular Therapy for Lysosomal Storage Disorders 129
Contents VII
5.3.2.1 Substrate Reduction Therapy 130
5.3.2.2 Pharmacological Chaperone Therapy 130
5.4 Concluding Remarks and Future Outlook 133
6 Neurotoxic Alkaloids from Cyanobacteria 139
Rashel V. Grindberg, Cynthia F. Shuman, Carla M. Sorrels, Josh Wingerd,
William H. Gerwick
6.1 Introduction 139
6.2 Neurotoxic Alkaloids of Principally Freshwater and Terrestrial
Cyanobacteria 141
6.2.1 Anatoxin-a, Homoanatoxin-a, Anatoxin-a(s), and Analogs 141
6.2.1.1 Anatoxin-a 142
6.2.1.2 Homoanatoxin-a 145
6.2.1.3 Anatoxin-a(s) 145
6.2.2 b-Methylaminoalanine 146
6.2.3 Saxitoxin 151
6.3 Neurotoxic Alkaloids of Marine Cyanobacteria 156
6.3.1 Antillatoxin A and B 156
6.3.2 Jamaicamide A, B, and C 158
6.3.3 Kalkitoxin 161
6.4 Conclusion 162
7 Lamellarin Alkaloids: Structure and Pharmacological Properties 171
Je´roˆme Kluza, Philippe Marchetti, Christian Bailly
7.1 Introduction 171
7.2 The Discovery of Lamellarins 172
7.3 Modulation of Multidrug Resistance 174
7.4 Antioxidant Properties 176
7.5 Inhibition of HIV-1 Integrase 176
7.6 Cytotoxicity 177
7.7 Topoisomerase I Inhibition 178
7.8 Targeting of Mitochondria and Proapoptotic Activities 180
7.9 Conclusion 184
8 Manzamine Alkaloids 189
Jiangnan Peng, Karumanchi V. Rao, Yeun-Mun Choo, Mark T. Hamann
8.1 Introduction 189
8.2 Manzamine Alkaloids from Marine Sponges 191
8.2.1 b-Carboline-containing Manzamine Alkaloids 191
8.2.1.1 Manzamine A Type 191
8.2.1.2 Manzamine B Type 195
8.2.1.3 Manzamine C Type 196
8.2.1.4 Other b-Carboline-containing Manzamines 196
8.2.2 Ircinal-related Alkaloids 198
8.3 Source and Large-scale Preparation of Manzamine Alkaloids 202
VIII Contents
8.3.1 Source of Manzamine Alkaloids 202
8.3.2 Large-scale Preparation of Manzamines 204
8.3.3 Supercritical Fluid Chromatography Separation of Manzamine
Alkaloids 205
8.4 Synthesis of Manzamine Alkaloids 206
8.4.1 Total Synthesis of Manzamine A and Related Alkaloids 206
8.4.2 Total Synthesis of Manzamine C 208
8.4.3 Total Synthesis of Nakadomarin A 214
8.4.4 Synthetic Studies of Manzamine Alkaloids 216
8.4.5 Studies on Biomimetic Synthesis 217
8.4.6 Synthesis of Manzamine Analogs 219
8.5 Biological Activities of Manzamines 220
8.5.1 Anticancer Activity 220
8.5.2 Antimalarial Activity 222
8.5.3 Antimicrobial and Antituberculosis Activity 224
8.5.4 Miscellaneous Biological Activities 225
8.6 Concluding Remarks 226
9 Antiangiogenic Alkaloids from Marine Organisms 233
Ana R. Diaz-Marrero, Christopher A. Gray, Lianne McHardy, Kaoru Warabi,
Michel Roberge, Raymond J. Andersen
9.1 Introduction 233
9.2 Purine Alkaloids 235
9.3 Terpenoid Derivatives 236
9.3.1 Avinosol 236
9.3.2 Cortistatins A–D 237
9.3.3 Squalamine 238
9.4 Motuporamines 240
9.5 Pyrrole-Imidazole Alkaloids: ‘‘Oroidin’’-Related Alkaloids 244
9.5.1 Agelastatin A 245
9.5.2 Ageladine A 247
9.6 Tyrosine-derived Alkaloids 250
9.6.1 Aeroplysinin-1 250
9.6.2 Psammaplin A 254
9.6.3 Bastadins 256
9.7 Tryptophan-derived Alkaloids 259
9.8 Ancorinosides 262
9.9 Concluding Remarks 263
10 A Typical Class of Marine Alkaloids: Bromopyrroles 271
Anna Aiello, Ernesto Fattorusso, Marialuisa Menna,
Orazio Taglialatela-Scafati
10.1 Introduction 271
10.2 Oroidin-like Linear Monomers 273
10.3 Polycyclic Oroidin Derivatives 278
Contents IX
10.3.1 C-4/C-10 Derivatives 278
10.3.2 N-1/C-9 Derivatives 281
10.3.3 N-7/C-11 þ N-1/C-12 Derivatives 281
10.3.4 N-7/C-11 þ C-4/C-12 Derivatives 284
10.3.5 N-1/C-12 þ N-7/C-12 Derivatives 285
10.3.6 N-1/C-9 þ C-8/C-12 Derivatives 285
10.4 Simple or Cyclized Oroidin-like Dimers 286
10.5 Other Bromopyrrole Alkaloids 291
10.6 Conclusions 296
11 Guanidine Alkaloids from Marine Invertebrates 305
Roberto G.S. Berlinck, Miriam H. Kossuga
11.1 Introduction 305
11.2 Modified Creatinine Guanidine Derivatives 305
11.3 Aromatic Guanidine Alkaloids 307
11.4 Bromotyrosine Derivatives 309
11.5 Amino Acid and Peptide Guanidines 310
11.6 Terpenic Guanidines 320
11.7 Polyketide-derived Guanidines 321
II New Trends in Alkaloid Isolation and Structure Elucidation 339
12 Analysis of Tropane Alkaloids in Biological Matrices 341
Philippe Christen, Stefan Bieri, Jean-Luc Veuthey
12.1 Introduction 341
12.2 Extraction 343
12.2.1 Plant Material 343
12.2.2 Supercritical Fluid Extraction 343
12.2.3 Microwave-assisted Extraction 344
12.2.4 Pressurized Solvent Extraction 345
12.2.5 Solid-phase Microextraction 345
12.2.6 Biological Matrices 346
12.3 Analysis of Plant Material and Biological Matrices 348
12.3.1 Gas Chromatography 348
12.3.2 High-performance Liquid Chromatography 355
12.3.3 Capillary Electrophoresis 359
12.3.4 Desorption Electrospray Ionization Mass Spectrometry 361
12.4 Conclusions 362
13 LC-MS of Alkaloids: Qualitative Profiling, Quantitative Analysis,
and Structural Identification 369
Steven M. Colegate, Dale R. Gardner
13.1 Introduction 369
13.2 LC-MS Overview 369
X Contents
13.2.1 Optimization 370
13.2.1.1 Modification of Mobile Phases and Ionization Parameters 370
13.2.1.2 HPLC Versus UPLC 372
13.2.1.3 Fluorinated HPLC Solid Phases 372
13.2.1.4 Reduction of Ion Suppression 373
13.3 Clinical Chemistry and Forensic Applications 374
13.3.1 Extraction and Analytical Considerations 375
13.3.2 Forensic Detection of Plant-derived Alkaloids 375
13.3.2.1 Plant-associated Intoxications 375
13.3.2.2 Illicit Drug Use: Multiple Reaction Monitoring 376
13.3.2.3 Quality Control of Herbal Preparations: APCI-MS 376
13.4 Metabolite Profiling and Structure Determination 376
13.4.1 LC-MS/MS Approaches to the Identification/Structural Elucidation
of Alkaloid Drug Metabolites 377
13.4.1.1 Tandem MS 377
13.4.1.2 Accurate Mass Measurement 378
13.4.1.3 Chemical Modification 378
13.4.2 Minimization of Sample Treatment 378
13.4.3 Structure Determination 380
13.4.3.1 Nudicaulins from Papaver nudicaule:
High-resolution MS 380
13.4.3.2 Endophyte Alkaloids: An MS Fragment Marker 380
13.5 Pyrrolizidine Alkaloids and Their N-Oxides 382
13.5.1 Solid Phase Extraction 383
13.5.2 Qualitative Profiling 383
13.5.2.1 Echium plantagineum and Echium vulgare 385
13.5.2.2 Senecio ovatus and Senecio jacobaea 387
13.5.3 Quantitative Analysis 392
13.5.3.1 Calibration Standards 393
13.5.3.2 Honey 394
13.6 Alkaloids from Delphinium spp. (Larkspurs) 395
13.6.1 Flow Injection (FI) Mass Spectrometry 396
13.6.1.1 Qualitative FI Analysis 397
13.6.1.2 Quantitative FI Analyses 398
13.6.1.3 Chemotaxonomy of Delphinium Species 399
13.6.2 LC-MS Analysis of Diterpene Alkaloids 400
13.6.2.1 Toxicokinetics and Clearance Times 400
13.6.2.2 Diagnosis of Poisoning 401
13.6.3 Structural Elucidation of Norditerpenoid Alkaloids 402
13.6.3.1 Stereochemical Indications 402
13.6.3.2 Isomeric Differentiation Using Tandem Mass
Spectrometry 403
13.6.3.3 Novel Diterpene Alkaloid Identification: Application of Tandem
Mass Spectrometry 405
13.7 Conclusions 405
Contents XI
14 Applications of 15N NMR Spectroscopy in Alkaloid Chemistry 409
Gary E. Martin, Marina Solntseva, Antony J. Williams
14.1 Introduction 409
14.1.1 15N Chemical Shift Referencing 409
14.1.2 15N Chemical Shifts 411
14.1.3 15N Reviews and Monographs 411
14.2 Indirect-Detection Methods Applicable to 15N 412
14.2.1 Accordion-optimized Long-range 1H–15N Heteronuclear Shift
Correlation Experiments 413
14.2.2 Pulse Width and Gradient Optimization 414
14.2.3 Long-range Delay Optimization 414
14.2.4 Establishing F1 Spectral Windows 416
14.3 15N Chemical Shift Calculation and Prediction 418
14.3.1 Structure Verification Using a 15N Content Database 418
14.3.2 15N NMR Prediction 419
14.3.3 Enhancing NMR Prediction With User-‘‘trained’’ Databases 420
14.3.4 Validating 15N NMR Prediction 420
14.4 Computer-assisted Structure Elucidation (CASE) Applications
Employing 15N Chemical Shift Correlation Data 422
14.5 Applications of 15N Spectroscopy in Alkaloid Chemistry 428
14.6 Applications of Long-range 1H–15N 2D NMR 430
14.6.1 Five-membered Ring Alkaloids 430
14.6.2 Tropane Alkaloids 436
14.6.3 Indoles, Oxindoles, and Related Alkaloids 437
14.6.3.1 Strychnos Alkaloids 437
14.6.3.2 Azaindoles 439
14.6.3.3 Indoloquinoline Alkaloids 439
14.6.3.4 Vinca Alkaloids 441
14.6.3.5 Other Indole Alkaloids 442
14.6.4 Carboline-derived Alkaloids 448
14.6.5 Quinoline, Isoquinoline, and Related Alkaloids 450
14.6.6 Benzo[c]phenanthridine Alkaloids 453
14.6.7 Pyrazine Alkaloids 456
14.6.8 Diazepinopurine Alkaloids 459
14.7 Pyridoacridine, Quinoacridine, and Related Alkaloids 460
14.8 Conclusions 465
III New Trends in Alkaloid Synthesis and Biosynthesis 473
15 Synthesis of Alkaloids by Transition Metal-mediated Oxidative
Cyclization 475
Hans-Joachim Kno¨lker
15.1 Silver(I)-mediated Oxidative Cyclization to Pyrroles 475
15.1.1 Synthesis of the Pyrrolo[2,1-a]isoquinoline Alkaloid Crispine A 477
XII Contents
15.1.2 Synthesis of the Indolizidino[8,7-b]indole Alkaloid
Harmicine 478
15.2 Iron(0)-mediated Oxidative Cyclization to Indoles 478
15.3 Iron(0)-mediated Oxidative Cyclization to Carbazoles 481
15.3.1 3-Oxygenated Carbazole Alkaloids 482
15.3.2 Carbazole-1,4-Quinol Alkaloids 483
15.3.3 Furo[3,2-a]carbazole Alkaloids 483
15.3.4 2,7-Dioxygenated Carbazole Alkaloids 485
15.3.5 3,4-Dioxygenated Carbazole Alkaloids 487
15.4 Palladium(II)-catalyzed Oxidative Cyclization to
Carbazoles 488
15.4.1 Carbazolequinone Alkaloids 489
15.4.2 Carbazomadurins and Epocarbazolins 492
15.4.3 7-Oxygenated Carbazole Alkaloids 493
15.4.4 6-Oxygenated Carbazole Alkaloids 495
16 Camptothecin and Analogs: Structure and Synthetic Efforts 503
Sabrina Dallavalle, Lucio Merlini
16.1 Introduction: Structure and Activity 503
16.2 Synthetic Efforts 507
17 Combinatorial Synthesis of Alkaloid-like Compounds In Search
of Chemical Probes of Protein–Protein Interactions 521
Michael Prakesch, Prabhat Arya, Marwen Naim, Traian Sulea,
Enrico Purisima, Aleksey Yu. Denisov, Kalle Gehring, Trina L. Foster,
Robert G. Korneluk
17.1 Introduction 521
17.2 Protein–Protein Interactions 523
17.3 Alkaloid Natural Products as Chemical Probes of Protein–Protein
Interactions 524
17.4 Indoline Alkaloid Natural Product-inspired
Chemical Probes 525
17.4.1 Indoline Alkaloid-inspired Chemical Probes 526
17.4.2 Tetrahydroquinoline Alkaloid-inspired Chemical Probes 528
17.5 Alkaloid Natural Product-inspired Small-molecule Binders to Bcl-2
and Bcl-XL and In Silico Studies 532
17.5.1 Alkaloid Natural Product-inspired Small-molecule Binders to
Bcl-XL and NMR Studies 533
17.5.2 Alkaloid Natural Product-inspired Small-molecule Probes
for XIAP 535
17.5.2.1 Cell Death Assay 535
17.5.2.2 Caspase-3 Activation Assay 536
17.5.2.3 Caspase-9 Release Assay 536
17.5.3 Summary and Future Outlook 536
17.6 Acknowledgments 538
Contents XIII
18 Daphniphyllum alkaloids: Structures, Biogenesis, and Activities 541
Hiroshi Morita, Jun’ichi Kobayashi
18.1 Introduction 541
18.2 Structures of Daphniphyllum Alkaloids 542
18.2.1 Daphnane-type Alkaloids 542
18.2.2 Secodaphnane-type Alkaloids 543
18.2.3 Yuzurimine-type Alkaloids 543
18.2.4 Daphnilactone A-type Alkaloids 543
18.2.5 Daphnilactone B-type Alkaloids 544
18.2.6 Yuzurine-type Alkaloids 544
18.2.7 Daphnezomines 545
18.2.8 Daphnicyclidins 551
18.2.9 Daphmanidins 557
18.2.10 Daphniglaucins 559
18.2.11 Calyciphyllines 560
18.2.12 Daphtenidines 560
18.2.13 Other Related Alkaloids 561
18.3 Biosynthesis and Biogenesis 564
18.3.1 Biosynthesis of Daphniphyllum Alkaloids 564
18.3.2 Biogenesis of the Daphnane and Secodaphnane Skeletons 564
18.3.3 Biogenesis of the Daphnezomines 565
18.3.4 Biogenesis of the Daphnicyclidins 568
18.3.5 Biogenesis of the Daphmanidins 569
18.3.6 Biogenesis of the Daphniglaucins 570
18.3.7 Biogenesis of the Calyciphyllines 573
18.3.8 Biogenesis of the Daphtenidines 573
18.4 Synthesis 575
18.4.1 Biomimetic Chemical Transformations 575
18.4.1.1 Transformation of an Unsaturated Amine to the Daphnane
Skeleton 575
18.4.1.2 Transformation of Daphnicyclidin D to Daphnicyclidins E and J 575
18.4.2 Biomimetic Total Synthesis 576
18.4.2.1 Methyl Homosecodaphniphyllate and Protodaphniphylline 576
18.4.2.2 Secodaphniphylline 579
18.4.2.3 Methyl Homodaphniphyllate and Daphnilactone A 580
18.4.2.4 Codaphniphylline 582
18.4.2.5 Bukittinggine 583
18.4.2.6 Polycyclization Cascade 583
18.5 Activities 585
18.6 Conclusions 586
19 Structure and Biosynthesis of Halogenated Alkaloids 591
Gordon W. Gribble
19.1 Introduction 591
19.2 Structure of Halogenated Alkaloids 591
XIV Contents
19.2.1 Indoles 591
19.2.2 Carbazoles 596
19.2.3 b-Carbolines 596
19.2.4 Tyrosines 598
19.2.5 Miscellaneous Halogenated Alkaloids 603
19.3 Biosynthesis of Halogenated Alkaloids 605
19.3.1 Halogenation Enzymes 605
19.3.2 Indoles 606
19.3.3 Biosynthesis of Halogenated Tyrosines 609
19.3.4 Biosynthesis of Miscellaneous Alkaloids 612
20 Engineering Biosynthetic Pathways to Generate Indolocarbazole
Alkaloids in Microorganisms 619
Ce´sar Sa´nchez, Carmen Me´ndez, Jose´ A. Salas
20.1 Introduction 619
20.2 Studies Made Before the Identification of Biosynthetic Genes 620
20.3 Identification of Genes Involved in Indolocarbazole Biosynthesis 621
20.3.1 Genes Involved in Rebeccamycin Biosynthesis 621
20.3.2 Genes Involved in Staurosporine Biosynthesis 625
20.3.3 Genes Involved in Biosynthesis of Other Indolocarbazoles 625
20.4 Indolocarbazole Biosynthetic Pathways and Their Engineering 626
20.4.1 Tryptophan Modification 626
20.4.2 Formation of Bisindole Pyrrole 627
20.4.3 Formation of Carbazole 630
20.4.4 Formation of the Sugar Moiety 632
20.4.4.1 Sugar Moieties in Rebeccamycin and AT2433 632
20.4.4.2 The Staurosporine Sugar Moiety 634
20.4.5 Regulation and Self-resistance 636
20.5 Perspectives and Concluding Remarks 637