Lead Molecules from Natural Products (eBook)

Cover 1
Contents 6
Preface to the Series 12
Preface 16
Reverse pharmacognosy: a new concept for accelerating natural drug discovery 20
Introduction 20
Pharmacognosy 22
Sample collection 23
Extraction 24
Activity-guided fractionation 24
Reverse pharmacognosy 24
Virtual chemical database 24
Target database 26
Selnergy™ 27
Ethnopharmacological database (ETPHDB) 28
Applications of Selnergy™ 30
Building therapeutic focused libraries 30
Building family focused libraries 30
Estimating biological properties of a compound library 30
Protein flexibility 30
Lead leveraging 31
Pharmacognosy and reverse pharmacognosy in natural drug discovery process 35
From pharmacognosy to lead 35
From reverse pharmacognosy to lead 35
Repositioning of compounds 36
Conclusions and perspectives 36
References 37
Effects of plant extracts on gene expression profiling: from macroarrays to microarray technology 40
Introduction 40
Treatment of K562 cells with M. oleifera extracts leads to changes in gene expression profile 43
Modifications of the gene expression profile in human K562 cells treated with M. oleifera and E. officinalis plant extracts 45
Validation of the macroarray data by RT-PCR 46
Conclusions and future perspectives 46
Acknowledgments 49
References 49
Effects of medicinal plant extracts on molecular interactions between DNA and transcription factors 54
Introduction 54
The electrophoretic mobility shift assay (EMSA) as a tool foridentification of inhibitors of protein–DNA interactions 57
Filter-binding assay for the screening of inhibitors of TF/DNA interactions 57
Plant extracts and inhibition of protein–DNA interactions 58
Future perspectives 59
Acknowledgments 59
References 59
Plants with antitumor properties: from biologically active molecules to drugs 64
Introduction 64
High-performance liquid chromatography (HPLC) 66
Recently developed HPLC-based methods 67
The SEPBOX for isolation of high amounts of pure compounds from plant extracts 68
Gas chromatography/mass spectrometry (GC/MS) 69
Plant extracts and plant-derived compounds in clinical trials 76
Future perspectives: biospecific interaction analysis (BIA) using surface plasmon resonance (SPR) and biosensor technologies for identification, isolation and characterization of bioactive compounds 77
Acknowledgements 79
References 79
Herbal extracts and compounds active against herpes simplex virus 84
Introduction 84
Epidemiology of herpes simplex virus 84
HSV structure and entry 85
Current anti-HSV therapy 85
Herpes simplex virus vaccine 86
Screening plants for antiviral activity 86
Plant extracts with activity against HSV 89
Plant compounds with anti-HSV activities 92
Modes of action of anti-HSV compounds 97
Topical microbicides 99
Discussion 100
References 102
Pharmacological modulation of cough reflex 106
Introduction 107
Definition of cough 107
Epidemiological data 107
Physiology of cough reflex 108
Larynx and pharynx – laryngopharyngeal cough 108
The tracheobronchial tree – tracheobronchial cough 109
Central nervous mechanisms in cough 111
Pathophysiology of cough 113
Cough and inflammation 113
Curiosities of cough reflex 114
Cough forms 115
Acute cough 115
Subacute cough 116
Chronic cough 116
Nonproductive cough 119
Psychogenic cough 121
Cough in asthma bronchiale 121
Productive cough 122
Painful cough 122
Choice of drugs 122
Drugs acting at the level of receptors 123
Drugs affecting the propagation of cough impulses in afferent nerves 124
Drugs modulating the central coordination of cough reflex 124
Drugs acting at the level of efferent nerves 125
Drugs affecting the effectors 125
Mucoactive substances 125
Demulcerative and hydrating drugs 125
References 126
Phytotherapy of cough 130
Introduction 130
Althaea officinalis L. (Fam. Malvaceae) 134
Emblica officinalis (Fam. Euphorbiaceae) 136
Foeniculum vulgare Mill. (Fam. Apiaceae) 138
Chelidonium majus L. (Fam. Papaveraceae) 138
Inula helenium L. (Fam. Asteraceae) 139
Malva sylvestris L. and Malva mauritiana L. (Fam. Malvaceae) 140
Papaver rhoeas L (Fam. Papaveraceae) 142
Plantago lanceolata L. (Fam. Plantaginaceae) 142
Polygonum aviculare L. (Fam. Polygonaceae) 143
Primula veris L. (Fam. Primulaceae) 144
Raphanus sativus L. var. niger (Mill.) (Fam. Brassicaceae) 145
Thymus vulgaris L. and Thymus serpyllum L. (Fam. Lamiaceae) 145
Verbascum densiflorum Bertoloni and Verbascum phlomoides L. (Fam. Scrophulariaceae) 146
References 147
The medicinal potential of black seed (Nigella sativa) and its components 152
Introduction 152
Chemical constituents and active principles in N. sativa seeds 153
Physiological effects of N. sativa and its component TQ 155
Antimicrobial and antiparasitic effects of N. sativa oil 158
Anticancer effects of N. sativa and its components 159
In vitro effects 159
In vivo effects 160
Antiinflammatory and immunomodulatory effects of N. sativa 162
Antioxidant and hepatoprotective effects of N. sativa 163
Analgesic and antinociceptive effects of N. sativa 165
Are N. sativa seeds or its components safe to consume? 166
Conclusions 166
Acknowledgments 167
References 167
Cyclin-dependent kinase inhibitors from natural sources: recent advances and future prospects for cancer treatment 174
Introduction 174
Traditional vs. advanced therapies of cancer 175
Cell cycle control and CDKs 176
Naturally derived CDKs used in cancer therapy 177
Flavopiridol 179
Staurosporines 180
Indirubins 181
Conclusions 182
References 182
Anticancer and medicinal properties of essential oil and extracts of East Mediterranean sage (salvia triloba) 188
Introduction 188
The sage plant 189
Essential oils of East Mediterranean sage 190
Therapeutic uses of East Mediterranean sage 191
Mode of action of sage essential oil 193
Anticancer effects of East Mediterranean sage 194
Acknowledgments 196
References 196
Marine organisms from Brazil as source of potential anticancer agents 200
Introduction 200
Brazilian marine biodiversity 202
Current research on marine natural products 203
IV. Clinical perspectives 210
V. Concluding remarks 211
References 211
Anticancer potential of Northeast Brazilian plants 216
Natural product-derived anticancer drug discovery 216
Current research on the antitumoral potential of Northeast Brazilian plants 218
Concluding remarks 228
References 228
Safety and efficacy of phytomedicines 232
Introduction 232
Types of products from medicinal plants sold in Brazil marketplace 234
Legal requirements for the use of phytomedicines in Brazil 235
Evaluation of safety and efficacy 236
Side effects and/or toxic reactions to phytomedicines 236
Phytomedicines currently in use or mentioned in scientific literature of natural products (traditional phytomedicines) 237
For new phytomedicines not in use or mentioned in literature 239
The phase I trials of phytomedicines 240
The phase II trials of phytomedicines 240
The phase III trials of phytomedicines 240
The phase IV trials of phytomedicines 241
Conclusion 241
References 241
Pharmacological and biochemical profiling of lead compounds from traditional remedies: the case of Croton cajucara 244
Introduction 245
Croton cajucara general pharmaco-chemical profiling 246
Seasonal variety of DCTN and its pharmacological importance 247
Hepatic toxicological evaluation of the aqueous extract 253
Antiproliferative effects of the isolated terpenoids and stem bark extracts 254
In vitro cytotoxic effects 254
In vivo antitumor effects 256
Genotoxic activity 258
Antigenotoxic activity 258
Croton cajucara phytochemical studies 259
NMR structural study of trans-dehydrocrotonin 259
NMR structural study of trans-crotonin 260
NMR structural study of aromatic acids 260
Experimental procedures 261
Chemical procedures 261
General experimental procedures 261
Chromatographic analysis 261
Plant material 261
Extraction and isolation of compounds 261
Oxidation of DCTN using singlet oxygen 262
Complementary spectroscopic data 263
Remaining compounds 263
Pharmacological procedures 264
Toxicological GPT methodology 264
Antiproliferative effects methodology 264
Plant material 264
In vivo experiments 264
Animals and tumors 264
Administration of drugs 265
Antitumor evaluation 265
In vitro experiments 265
Genotoxic and antigenotoxic activity 265
Drugs 265
Protocols 265
Micronucleus assay 265
Chromosomal aberration assay 266
Cytological analysis 266
Statistical analysis 266
Antiulcer activity 266
Animals 266
Antiulcer evaluation 266
Determination of gastric acid secretion 267
Oxyntic gland preparation 267
Gland viability 267
14C-Aminopyrine accumulation/uptake 267
Gastrointestinal transit 267
Drugs 268
Statistics 268
Conclusions 268
Acknowledgments 269
References 269
Antihypertensive peptides from natural resources 274
Background 274
Renin–angiotensin–aldosterone system 275
Target for RAS regulation 275
Preparation and identification of ACE inhibitory peptides from natural proteins 277
Antihypertensive effect of natural peptides with in vitro ACE inhibitory activity 283
Absorption and antihypertensive mechanism of natural ACE inhibitory peptides 285
References 288
Xanthones as therapeutic agents: chemistry and pharmacology 292
Introduction 292
Distribution in nature 293
Obtaining of xanthones 293
Classification 293
Simple oxygenated xanthenes 293
Glycoside xanthenes 296
Prenylated xanthones 297
Xanthonolignoids 297
Miscellaneous 298
Methods of isolation and structural investigation 298
Use of some plant sources containing xanthones 300
Biosynthesis of xanthones 302
Acetate polymalonic route 302
Mixed shikimate acetate pathway 302
Synthesis of xanthones 303
Demethylation of xanthones 306
Synthesis of prenylated xanthones 306
O-prenylated xanthones 306
Bioactivities of xanthones 307
Action on the central nervous system (CNS) 308
Cardiovascular activity 308
Anti-fungal and anti-bacterial activities 309
Cytotoxic and anti-tumoral properties 309
Anti-diabetic property 310
Hepatoprotective activity 310
Anti-parasitic activity 310
Anti-inflammatory effects 310
HIV-inhibitory activity 311
P-glycoprotein inhibitory property 311
Conclusion 314
References 314
Inhibition of immunodeficiency type-1 virus (HIV-1) life cycle by medicinal plant extracts and plant-derived compounds 318
Introduction 318
Comparative in vitro effects of extracts from medicinal plants and AZT 321
From unfractionated plant extracts to pure compounds and from the laboratory to the clinic 322
The HIV-1 life cycle and the mechanism of action of anti-HIV compounds from medicinal plants 324
Inhibition of transcription factors involved on HIV-1 transactivation 324
Conclusions 326
Acknowledgments 326
References 327
Anticancer properties of saffron, Crocus sativus Linn. 332
Introduction 332
Tumouricidal properties 334
Chemopreventive activity 336
Cellular effects 337
Bioactive compounds from corm 340
Immuno-stimulating activity 341
Biotechnological production 342
Conclusions 343
Acknowledgments 344
References 345
Lead compounds and drug candidates from some Turkish plants for human health 350
Introduction 350
Antiacetylcholinesterase compounds 352
Lycopodium species 352
Amaryllidaceae alkaloids 353
Isoquinoline alkaloids 355
Steroidal alkaloids 358
Anticholinergic compounds 359
Antihypertensive compounds 360
Antithrombocyter compounds 361
Antimalarial compounds 361
Anti-inflammatory compounds 362
Paeonia daurica 362
Iris germanica 363
Antibacterial compounds 364
Steroidal alkaloids 364
Isoflavonoids 366
Conclusion 367
References 367
Molecular design of multifunctional anti-Salmonella agents based on natural products 372
Introduction 372
Antibacterial activity 373
Test strains 373
Medium 374
Precultivation 374
Antibacterial assay 374
Combination study 374
Time kill study 374
(2E)-Alkenals 374
Modes of antibacterial action 380
Combination effects 382
Molecular design 383
Alkyl gallates 384
Conclusions 388
Acknowledgments 389
References 389
Plant growth inhibitory activities by secondary metabolites isolated from Latin American flora 392
Introduction 392
Terpenoids 394
Monoterpenes 394
Diterpenes 394
Sesquiterpenes and sesquiterpene lactones 395
Nortriterpenes (Limonoids) 398
Phenolics 402
Discussion 406
Monocot and Dicot Growth 407
Dry weight of monocotyledonous and dicotyledonous plants 413
Seed respiration during seed germination 414
Chloroplasts and mitochondrial inhibition 416
Radical scavenging properties and antioxidant activity 418
Concluding remarks 418
Material and methods 419
Plant material 419
Chemicals and solvents 420
Apparatus 420
General experimental procedures 420
Bioactivity-guided isolation and purification of acetophenones, tremetones, and their derivatives 420
Derivatization of compounds 421
Post- and pre-emergence activities 421
Seeds germination bioassays 421
Growth bioassays 422
Seed respiration 422
Preparation of thylakoid membranes 422
Measurement of proton uptake and ATP synthesis 422
Measurement of electron transport 422
Determination of mitochondrial oxygen consumption 423
Reduction of 2,2'-diphenyl-1-picrylhydrazyl [2,2'-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl DPPH] Radical
Bleaching of crocin 424
Statistical analysis 424
Acknowledgments 424
References 425
Metabolomics – systematic studies of the metabolic profiling 430
What is metabolomics? 430
What is the rationale for doing this analysis? 431
Analytical technologies used in phytometabolomics 431
Separation methods 432
Detection methods 432
Analysis of the data from different MS techniques 434
Major applications of the metabolomics 435
Genomics and metabolomics 436
Conclusion 437
References 437
Contributors 440
Subject Index 444