Natural product chemistry for drug discovery

Library	Item Barcode	Call Number	Material Type	Item Category 1	Status
Searching... PSZ JB	30000010253787	RS160 N375 2010	Open Access Book	Book	Searching... Unknown
Searching... PSZ JB	30000010251668	RS160 N375 2010	Open Access Book	Book	Searching... Unknown
Searching... PSZ KL	30000010241825	RS160 N375 2010	Open Access Book	Gift Book	Searching... Unknown

Natural Product Chemistry for Drug Discovery provides a comprehensive summary of where natural product chemistry is today in drug discovery. The book covers emerging technologies and case studies and is a source of up-to-date information on the topical subject of natural products. The authors, all experts in their respective fields, provide compelling arguments as to why naturel products should be considered important tools in the drug discovery process. The book will appeal across the board from scientists to professionals, postgraduates and industrial chemists. The case studies selected for inclusion highlight recently marketed drugs and development candidates that have been derived from natural products. These 'real-life' examples show how new technologies, such as advances in screening, isolation, dereplication and prefractionation, have significantly enhanced the discovery process.

Author Notes

Dr A.D. Buss graduated from the Royal Institute of Chemistry before receiving his MSc from the University of East Anglia and then a PhD from the University of Cambridge. He started his career in the pharmaceutical industry with Pfizer before moving to Schering Agrochemicals as a Team Leader. In 1989, he joined Glaxo as Research Manager prior to becoming Head of the Natural Products Discovery Department and, finally, Research Unit Head, Bioprocessing, in 1995. During this period, Dr. Buss served as Chairman of the GlaxoWellcome (UK) Research Management Team and Chairman of the Joint Project Team (combinatorial polyketide biosynthesis) for what was GlaxoWellcome's largest research collaboration with the University of Cambridge. In 2000, he became head of the Centre for Natural Product Research at the Institute of Molecular and Cell Biology in Singapore and, on the Centre's privatisation to MerLion Pharmaceuticals in May 2002, became its President and Chief Executive Officer. Dr Buss is the author or co-author of over fifty peer reviewed scientific publications. Dr Mark S. Butler received his BSc (Hons) and PhD from The University of Melbourne. After postdoctoral work at the Arizona State University, he joined the Queensland Pharmaceutical Research Institute (now Natural Product Research). He then moved to Singapore to lead the Natural Product Chemistry group at the Centre of Natural Product Research (CNPR), which was part of the Institute of Molecular and Cell Biology (IMCB). In 2002, CNPR privatized to become MerLion Pharmaceuticals where his present position is Director of Natural Product Chemistry. He has contributed to over 40 papers on various aspects of natural products chemistry and, in 2002, was awarded the Matt Suffness (Young Investigator) Award by the American Society of Pharmacognosy.

Section 1 Introduction to Natural Products for Drug Discovery
Chapter 1 Natural Products as Drugs and Leads to Drugs: The Historical PerspectiveDavid J. Newman and Gordon M. Cragg
1 Ancient History (> 2900 BCE to 1800 CE)	p. 3
2 The Initial Influence of Chemistry upon Drug Discovery	p. 6
2.1 Alkaloids	p. 6
2.2 Aspirin	p. 8
2.3 Digitalis	p. 9
3 20th and 21st Century Drugs/Leads from Nature	p. 10
3.1 Antibacterial and Antifungal Antibiotics	p. 10
3.2 Antiviral Agents	p. 19
3.3 Natural Product Based Antitumour Agents	p. 21
4 Final Comments	p. 23
References	p. 24
Chapter 2 Chemical Space and the Difference Between Natural Products and SyntheticsSheo B. Singh and J. Chris Culberson
1 Introduction	p. 28
2 Sources of Organic Compounds and Drug Leads	p. 29
2.1 Natural Products	p. 29
2.2 Natural Product Derivatives	p. 29
3 Synthetic Compounds	p. 30
3.1 Synthetic Compound Libraries	p. 30
3.2 Combinatorial Libraries	p. 30
3.3 Diversity-Oriented Synthetic (DOS) Libraries	p. 31
3.4 Fragment Libraries	p. 31
4 Lipinski's "Rule, of Five" for Orally Active Drugs	p. 32
5 Assessment of Diversity of Libraries with Respect to Drugs	p. 33
5.1 Molecular Weight	p. 34
5.2 Distribution of Atom Types: H-bond Donors and Acceptors	p. 35
5.3 Lipophilicities (Log P)	p. 37
5.4 Chiral Centres	p. 37
5.5 Rotatable Bonds, Unsaturations, Rings, Chains and Ring Topology	p. 38
6 Principal Component Analysis (PCA)	p. 39
7 Conclusions	p. 40
References	p. 42
Chapter 3 Mechanism of Action StudiesJames J. La Clair
1 Introduction	p. 44
2 Some Like It Hot: Esperamicin A 1 Neocarzinostatin and Related Enediyne Antibiotics	p. 45
3 To Catch a Mockingbird: Taxol, Epothilone and the Microtubule	p. 47
4 Notorious: Jasplakinolide, Alias Jaspamide and Actin	p. 51
5 Invasion of the Pathway Snatchers: Artemisinin	p. 53
6 Once Upon a Time in the Immune System: FK-506, Cyclosporin A and Rapamycin	p. 55
7 Back to the Cytoskeleton: the Phorboxazoles	p. 56
8 It's a Wonderful Target: VTPase and its Targeting by Apicularen A, Salicylihalamide A and Palmerolide A	p. 59
9 Double Indemnity: Bistramide A	p. 61
10 The Matrix: the Pladienolides and Splicing Factor SF3b	p. 62
11 The Unusual Suspects: (+)-Avrainvillamide	p. 65
12 Close Encounters of a Third Kind: Ammosamides, Blebbestatin and Myosin	p. 67
13 The End	p. 69
References	p. 69
Section 2 Sources of Compounds
Chapter 4 The Convention on Biological Diversity and its Impact on Natural Product ResearchGeoffrey A. Cordell
l Introduction	p. 81
2 Historical Perspective	p. 85
3 The Convention on Biological Diversity	p. 87
4 Implementation and Regulatory Outcomes of the CBD	p. 92
5 Assessment of Impact	p. 95
5.1 An Overview and Some Examples	p. 95
5.2 An Informal Survey	p. 100
5.3 Survey Results	p. 101
5.4 Survey Overview	p. 116
6 The TRIPS Agreement and the CBD	p. 116
7 Other Aspects and Outcomes	p. 123
7.1 The International Cooperative Biodiversity Group Programme	p. 125
8 Some Recommendations	p. 127
9 A Web of Interconnectedness	p. 130
10 A Different World	p. 131
11 Conclusions	p. 133
Acknowledgements	p. 134
References	p. 135
Chapter 5 Plants: Revamping the Oldest Source of Medicines with Modern ScienceGiovanni Appendino and Federica Pollastro
1 Introduction	p. 140
2 Plant Secondary Metabolites vs. Secondary Metabolites of Other Origin	p. 143
3 Unnatural Sources of Plant Secondary Metabolites	p. 146
4 Critical Issues in Plant-based Natural Product Drug Discovery	p. 149
4.1 Intellectual Property (IP) Issues	p. 149
4.2 Pieiotropy and Synergy	p. 151
Extract Libraries vs. Fraction (Peak) Libraries vs. Compound Libraries	p. 153
4.4 Removal of Interfering Compounds	p. 155
5 Selection Strategies for Plant-Based Natural Product Drug Discovery	p. 156
5.1 Ethnopharmacology	p. 156
5.2 Zoopharmacy and Animal Toxicology	p. 157
5.3 Traditional Medicine	p. 158
5.4 Dietary Plants and Spices	p. 159
6 The Pharmaceutical Relevance of Plants	p. 161
6.1 Plants as a Source of Lead Structures and Drugs	p. 161
6.2 Plants as a Source of Standardised Extracts	p. 163
7 Conclusions	p. 167
References	p. 168
Chapter 6 Macromarines: A Selective Account of the Potential of Marine Sponges, Molluscs, Soft Corals and Tunicates as a Source of Therapeutically Important Molecular StructuresJennifer Carroll and Phillip Crews
1 Introduction	p. 174
1.1 Macroorganisms: Outstanding Success in Producing Viable Drug Leads	p. 175
1.2 Setting that Ara A and Ara C Story Straight	p. 175
1.3 The Potential Role of Invertebrate Associated Microorganisms and Secondary Metabolite Production	p. 176
1.4 Macromarine Evolution	p. 176
2 Sponges	p. 177
2.1 Natural History of Sponges-a Primitive Phylum with Remarkable Biosynthetic Capabilities	p. 177
3 Molluscs	p. 186
3.1 Natural History of Molluscs-the Source of Numerous Preclinical Drug Leads	p. 186
4 Soft Corals	p. 189
4.1 Natural History of Cnidarians-the "Stinging Nettle" of the Sea	p. 189
5 Tunicates	p. 192
5.1 Natural History of Tunicates-Our Closest Marine Invertebrate Relations	p. 192
6 Conclusions	p. 194
References	p. 195
Chapter 7 Microorganisms: Their Role in the Discovery and Development of MedicinesCedric Pearce and Peter Eckard and Iris Gruen-Wollny and Friedrich G. Hansske
1 Introduction	p. 215
2 Bacteria	p. 218
3 Fungi	p. 220
4 Terrestrial and Marine Microorganisms	p. 221
5 Microbial Cultural Collection	p. 222
6 Evidence for "Uncultivable" Microbes	p. 223
7 Metagenomic Approach to Access Uncultivable Microbes	p. 224
8 Culturing Techniques to Produce Secondary Metabolites	p. 225
9 Evidence for New Biosynthetic Pathways in Known Microbes	p. 227
10 Genetic Pathway Engineering and Modulation of Post-translational Modification to Generate Novel Compounds	p. 227
11 Microbial Secondary Metabolits with Unique Biological Activity and Chemical Diversity	p. 228
l2 Microbial Seconday Metabolites with Unique Pharmacological Activity	p. 231
13 Conclusions	p. 233
Structures Discussed in Tables 7.2 and 7.3	p. 233
References	p. 236
Section 3 Advances in Technology
Chapter 8 Advances in Biological Screening for Lead DiscoveryChristian N. Parker and Johannes Ottl and Daniela Gabriel and Ji-Hu Zhang
1 Introduction	p. 245
1.1 Natural Product Screening and the Development of HTS	p. 247
1.2 Chapter Objectives	p. 247
2 Types of HTS Assays	p. 247
2.1 In vitro Biochemical Assays	p. 248
2.2 Cell-based Assays	p. 255
2.3 Modelling to Identify False Positives and Negatives	p. 261
3 Emerging Trends	p. 262
3.1 New HTS Approaches	p. 262
Acknowledgements	p. 265
References	p. 265
Chapter 9 Advances in Instrumentation, Automation, Dereplication and PrefractionationTim S. Bugni and Mary Kay Harper and Malcolm W.B. McCulloch and Emily L. Whitson
1 Introduction	p. 272
2 Dereplication	p. 274
3 Extraction	p. 275
4 Prefractio nation	p. 276
5 Isolation and Purification	p. 278
5.1 Automated Purification	p. 279
6 HPLC Separation Technologies	p. 279
7 Mass Spectrometry	p. 282
8 NMR	p. 285
8.1 Probe Technology	p. 285
8.2 Structure Elucidation	p. 287
8.3 Methods for Fast NMR	p. 288
8.4 Automated Structure Elucidation	p. 290
8.5 Configuration by NMR	p. 291
8.6 Residual Dipolar Couplings	p. 292
9 Conclusions	p. 292
References	p. 293
Chapter 10 Natural Product Combinatorial Biosynthesis: Promises and RealitiesDaniel W. Udwary
1 Introduction	p. 299
2 A Brief History of Natural Product Biosynthesis	p. 300
3 Promises	p. 304
4 Realities	p. 307
5 Future Biotechnological Promises	p. 312
References	p. 314
Section 4 Natural Products in Clinical Development
Chapter 11 A Snapshot of Natural Product-Derived Compounds in Late Stage Clinical Development at the End of 2008Mark S. Butler
1 Introduction	p. 321
2 NP-derived Drugs Launched in the Last Five Years	p. 324
3 Late Stage NDAs and Clinical Candidates	p. 327
3.1 Antibacterial	p. 327
3.2 Oncology	p. 332
3.3 Other Therapeutic Areas	p. 340
4 Conclusions and Outlook	p. 342
References	p. 343
Chapter 12 From Natural Product to Clinical Trials: NPI-0052 (Salinosporamide A), a Marine Actinomycete-Derived Anticancer AgentKin S. Lam and G. Kenneth Lloyd and Saskia T. C. Neuteboom and Michael A. Palladino and Kobi M. Sethna and Matthew A. Spear and Barbara C. Potts
1 Introduction	p. 355
1.1 Bioprospecting Marine Actinomycetes and the Discovery of Salinispora and NPI-0052	p. 355
1.2 The Ubiquitin-Proteasome, System as a Target for Drug Development	p. 356
2 Mechanism of Action	p. 358
3 Microbiology of Salinispora tropica, Fermentation and Scale-up	p. 359
4 Structural Biology and Structure-Activity Relation ship Studies	p. 361
5 Translational Biology	p. 363
6 IND-Enabling Studies of NPI-005	p. 364
7 API Manufacturing	p. 365
8 Formulation Development and Drug Product Manufacturing	p. 366
9 Pharmacodynamics	p. 367
10 Pharmacokinetics	p. 368
11 Clinical Trials	p. 368
12 Concluding Remarks	p. 370
Acknowledgements	p. 370
References	p. 370
Chapter 13 From Natural Product to Clinical Trials: Bevirimat, a Plant-Derived Anti-AIDS DrugKeduo Qian and Theodore J. Nitz and Donglei Yu and Graham P. Allaway and Susan L. Morris-Natschke and Kuo-Hsiung Lee
1 Introduction	p. 374
2 Bioactivity-directed Fractionation and Isolation	p. 375
3 Lead Identification	p. 375
4 Lead Optimisation and SAR Study	p. 377
4.1 Modification of the BA Triterpene Skeleton	p. 377
4.2 Modification on C-3 Position of BA	p. 378
4.3 Introduction of C-28 Side Chain into BA	p. 382
4.4 Bifunctional BA Analogues-Potential for Maturation Inhibitor Development	p. 383
5 Mechanism of Action Studies of Bevirimat	p. 384
6 Preclinical Studies of Bevirimat	p. 385
7 Clinical Trials and Current Status of Bevirimat	p. 387
8 Conclusions	p. 388
Acknowledgements	p. 388
References	p. 388
Section 5 Case Studies of Marketed Natural Product-derived Drugs
Chapter 14 DaptomycinRichard H. Baltz
1 Introduction	p. 395
2 Discovery of A21987C and Daptomycin	p. 396
2.1 Enzymatic Cleavage of the Fatty Acid Side Chain	p. 396
2.2 Chemical Modifications of the A21978C Core Peptide	p. 397
3 Biosynthesis	p. 397
3.1 Analysis of the Daptomycin Biosynthetic Gene Cluster	p. 397
3.2 Daptomycin Structure	p. 398
4 Mechanism of Action Studies	p. 399
4.1 Daptomycin Resistant Mutants	p. 400
5 Antibacterial Activities	p. 401
5.1 In vitro Activities	p. 401
5.2 In vivo Activities in Animal Models	p. 402
6 Clinical Studies	p. 402
6.1 Eli Lilly and Company	p. 402
6.2 The Passing of the Baton	p. 403
6.3 Cubist Pharmaceuticals	p. 403
7 Lessons Learned	p. 404
8 Epilogue	p. 405
References	p. 405
Chapter 15 MicafunginAkihiko Fujie and Shuichi Tawara and Seiji Hashimoto
1 Introduction	p. 410
1.1 New Antifungal Compounds Discovered at Fujisawa (a Predecessor of Astellas Pharma Inc.)	p. 411
1.2 1,3-ß-Glucan Synthase Inhibition and Echinocandins	p. 413
2 From the Discovery of FR901379 to Clinical Studies of FK463 (Micafungin)	p. 414
2.1 Discovery of FR901379	p. 414
2.2 Generation of Lead Compound FR131535	p. 418
2.3 Lead Optimisation Leading to the Discovery FK463 12,13	p. 421
2.4 Preclinical Studies of FK463	p. 425
2.5 Industrial Manufacturing of Micafungin	p. 426
2.6 Clinical Studies of FK463	p. 426
3 Conclusions	p. 427
Acknowledgements	p. 427
References	p. 427
Subject Index

Available:*

On Order

Summary

Summary

Author Notes

Table of Contents