Natural Products in Medicinal Chemistry E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Serie: Methods and Principles in Medicinal Chemistry
• Sprache: Englisch

Seitenzahl: 1082

Veröffentlichungsjahr: 2013

Beschreibung

The inspiration provided by biologically active natural products to conceive of hybrids, congeners, analogs and unnatural variants is discussed by experts in the field in 16 highly informative chapters. Using well-documented studies over the past decade, this timely monograph demonstrates the current importance and future potential of natural products as starting points for the development of new drugs with improved properties over their progenitors. The examples are chosen so as to represent a wide range of natural products with therapeutic relevance among others, as anticancer agents, antimicrobials, antifungals, antisense nucleosides, antidiabetics, and analgesics. From the content: * Part I: Natural Products as Sources of Potential Drugs and Systematic Compound Collections * Part II: From Marketed Drugs to Designed Analogs and Clinical Candidates * Part III: Natural Products as an Incentive for Enabling Technologies * Part IV: Natural Products as Pharmacological Tools * Part V: Nature: The Provider, the Enticer, and the Healer

Leseprobe

Contents

Cover

Related Titles

Title Page

Copyright

List of Contributors

Preface

Personal Foreword

Part One: Natural Products as Sources of Potential Drugs and Systematic Compound Collections

Chapter 1: Natural Products as Drugs and Leads to Drugs: An Introduction and Perspective as of the End of 2012

1.1 Introduction

1.2 The Sponge-Derived Nucleoside Link to Drugs

1.3 Initial Recognition of Microbial Secondary Metabolites as Antibacterial Drugs

1.4 β-Lactams of All Classes

1.5 Tetracycline Derivatives

1.6 Glycopeptide Antibacterials

1.7 Lipopeptide Antibacterials

1.8 Macrolide Antibiotics

1.9 Pleuromutilin Derivatives

1.10 Privileged Structures

1.11 The Origin of the Benzodiazepines

1.12 Benzopyrans: A Source of Unusual Antibacterial and Other Agents

1.13 Multiple Enzymatic Inhibitors from Relatively Simple Natural Product Secondary Metabolites

1.14 A Variation on BIOS: The “Inside–Out” Approach

1.15 Other Privileged Structures

1.16 Privileged Structures as Inhibitors of Protein–Protein Interactions

1.17 Underprivileged Scaffolds

1.18 So Where Should One Look in the Twenty-First Century for Novel Structures from Natural Sources?

1.19 Conclusions

References

Chapter 2: Natural Product-Derived and Natural Product-Inspired Compound Collections

2.1 Introduction

2.2 Modern Approaches to Produce Natural Product Libraries

2.3 Prefractionated Natural Product Libraries

2.4 Libraries of Pure Natural Products

2.5 Semisynthetic Libraries of Natural Product-Derived Compounds

2.6 Synthetic Libraries of Natural Product-Inspired Compounds

2.7 Compound Collections with Carbocyclic Core Structures

2.8 Compound Collections with Oxa-Heterocyclic Scaffolds

2.9 Compound Collections with Aza-Heterocyclic Scaffolds

2.10 Macrocyclic Compound Collections

2.11 Outlook

References

Part Two: From Marketed Drugs to Designed Analogs and Clinical Candidates

Chapter 3: Chemistry and Biology of Epothilones

3.1 Introduction: Discovery and Biological Activity

3.2 Synthesis of Natural Epothilones

3.3 Synthesis and Biological Activity of Non-Natural Epothilones

3.4 Conformational Studies and Pharmacophore Modeling

3.5 Conclusions

References

Chapter 4: Taxol, Taxoids, and Related Taxanes

4.1 Introduction and Historical Background

4.2 Mechanism of Action and Drug Resistance

4.3 Structure–Activity Relationships (SAR) of Taxol

4.4 Structural and Chemical Biology of Taxol

4.5 New-Generation Taxoids from 10-DAB

4.6 Taxoids in Clinical Development

4.7 New Applications of Taxanes

4.8 Conclusions and Perspective

References

Chapter 5: Camptothecin and Analogs

5.1 Introduction

5.2 Biology Activity

5.3 Camptothecin in Clinical Use and Under Clinical Trials

5.4 Chemistry

5.5 Structure–Activity Relationship

5.6 Xenograft Studies

5.7 Prodrug/Targeting

5.8 Developments of Modern Chromatographic Methods Applied to CPT

5.9 Conclusions and Perspectives

References

Chapter 6: A Short History of the Discovery and Development of Naltrexone and Other Morphine Derivatives

6.1 Introduction

6.2 History and Development

6.3 Pharmacology

6.4 Structure–Activity Relationship of Morphine and its Analogs

6.5 Conclusions and Outlook

References

Chapter 7: Lincosamide Antibacterials

7.1 Introduction

7.2 Mechanism of Action

7.3 Antibacterial Spectrum

7.4 Resistance

7.5 Pseudomembranous Colitis

7.6 Next-Generation Lincosamides

7.7 Conclusions

References

Chapter 8: Platensimycin and Platencin

8.1 Introduction and Historical Background

8.2 Discovery and Bioactivities of Platensimycin and Platencin

8.3 Total and Formal Syntheses of Platensimycin

8.4 Total and Formal Syntheses of Platencin

8.5 Analogs of Platensimycin and Platencin

8.6 Conclusions and Perspective

Acknowledgment

References

Chapter 9: From Natural Product to New Diabetes Therapy: Phlorizin and the Discovery of SGLT2 Inhibitor Clinical Candidates

9.1 Introduction

9.2 Phlorizin: A Drug Lead from Apple Trees

9.3 Phlorizin: Mechanism of Action

9.4 Phlorizin, SGLTs, and Diabetes

9.5 Phlorizin Analogs: O -Glucosides

9.6 Phlorizin Analogs: C -Glucosides

9.7 C-Glucosides: Aglycone Modifications

9.8 C-Glucosides: Sugar Modifications

9.9 Conclusions

References

Chapter 10: Aeruginosins as Thrombin Inhibitors

10.1 Introduction

10.2 Targeting the Blood Coagulation Cascade

10.3 Structure of Thrombin

10.4 The Aeruginosin Family

10.5 Mimicking Nature

10.6 Conclusions

References

Part Three: Natural Products as an Incentive for Enabling Technologies

Chapter 11: Macrolides and Antifungals via Biotransformation

11.1 Introduction to Polyketides and Their Activity

11.2 Mechanism of Polyketide Biosynthesis

11.3 Conclusions

Acknowledgments

References

Chapter 12: Unnatural Nucleoside Analogs for Antisense Therapy

12.1 Nature Uses Nucleic Acid Polymers for Storage, Transfer, Synthesis, and Regulation of Genetic Information

12.2 The Antisense Approach to Drug Discovery

12.3 The Medicinal Chemistry Approach to Oligonucleotide Drugs

12.4 Structural Features of DNA and RNA Duplexes

12.5 Improving Binding Affinity of Oligonucleotides by Structural Mimicry of RNA

12.6 Improving Binding Affinity of Oligonucleotides by Conformational Restraint of DNA – the Bicyclo- and Tricyclo-DNA Class of Nucleic Acid Analogs

12.7 Improving Binding Affinity of Oligonucleotides by Conformational Restraint of the Phosphodiester Backbone –α,β-Constrained Nucleic Acids

12.8 Naturally Occurring Backbone Modifications

12.9 Naturally Occurring Heterocycle Modifications

12.10 Outlook

References

Chapter 13: Hybrid Natural Products

13.1 Introduction

13.2 Staurosporines (Amino Acid–Sugar Hybrids)

13.3 Lincomycins (Amino Acid–Sugar Hybrids)

13.4 Madindolines (Amino Acid–Polyketide Hybrids)

13.5 Kainoids (Amino Acid–Terpene Hybrids)

13.6 Benanomicin–Pradimicin Antibiotics (Sugar–Polyketide Hybrids)

13.7 Angucyclines (Sugar–Polyketide Hybrids)

13.8 Furaquinocins (Polyketide–Terpene Hybrids)

13.9 Conclusions

References

Part Four: Natural Products as Pharmacological Tools

Chapter 14: Rethinking the Role of Natural Products: Function-Oriented Synthesis, Bryostatin, and Bryologs

14.1 Introduction

14.2 Introduction to Function-Oriented Synthesis

14.3 Introduction to Bryostatin

14.4 Bryostatin Total Syntheses

14.5 Application of FOS to the Bryostatin Scaffold

14.6 Conclusions

References

Chapter 15: Cyclopamine and Congeners

15.1 Introduction

15.2 The Discovery of Cyclopamine

15.3 Accessibility of Cyclopamine

15.4 The Hedgehog Signaling Pathway [42–50]

15.5 Medical Relevance of Cyclopamine and the Hedgehog Signaling Pathway

15.6 Further Modulators of the Hedgehog Signaling Pathway

15.7 Summary and Outlook

References

Part Five: Nature: The Provider, the Enticer, and the Healer

Chapter 16: Hybrids, Congeners, Mimics, and Constrained Variants Spanning 30 Years of Natural Products Chemistry: A Personal Retrospective

16.1 Introduction

16.2 Structure-Based Organic Synthesis

16.3 Nucleosides

16.4 β-Lactams

16.5 Morphinomimetics

16.6 Histone Deacetylase Inhibitors

16.7 Pactamycin Analogs

16.8 Aeruginosins: From Natural Products to Achiral Analogs

16.9 Avermectin B 1a and Bafilomycin A1

16.10 Bafilomycin A1

16.11 3-N,N -Dimethylamino Lincomycin

16.12 Oxazolidinone Ketolide Mimetics

16.13 Epilogue

Acknowledgments

References

Index

Related Titles

Methods and Principles in Medicinal Chemistry

Edited by R. Mannhold, H. Kubinyi, G. Folkers

Editorial Board

H. Buschmann, H. Timmerman, H. van de Waterbeemd, T. Wieland

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Medicinal Chemistry Approaches to Personalized Medicine

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List of Contributors

Karl-Heinz Altmann

ETH Zürich

Institute of Pharmaceutical Sciences

Department of Chemistry and Applied Biosciences

Wolfgang-Pauli-Str. 10

HCI H 405

8093 Zürich

Switzerland

Gordon M. Cragg

DCTD and FNLCR

Natural Products Branch

Developmental Therapeutics Program

Frederick, MD 21702

USA

Juan R. Del Valle

Moffitt Cancer Center

Drug Discovery Department

12902 Magnolia Dr.

Tampa, FL 33612

USA

Alison C. Donnelly

Stanford University

Departments of Chemistry and Chemical and Systems Biology

337 Campus Dr

Stanford, CA 94305

USA

Alice L. Erwin

Erwin Consulting

110 College Avenue #2

Somerville, MA 02144

USA

Arun K. Ghosh

Purdue University

Department of Chemistry and

Department of Medicinal Chemistry

560 Oval Drive

West Lafayette, IN 47907-2084

USA

Giuseppe Giannini

RD Corporate Sigma-Tau Industrie

Farmaceutiche Riunite S.p.A.

00040 Pomezia, Rome

Italy

Athanassios Giannis

University of Leipzig

Institute for Organic Chemistry

Johannisallee 29

04103 Leipzig

Germany

Stephen Hanessian

Université de Montréal

Department of Chemistry

C.P. 6128, Succursale Centre-Ville

Montréal, Québec H3C 3J7

Canada

Philipp Heretsch

Rice University

BioScience Research Collaborative

6500 Main Street

Houston, TX 77030

USA

Tomas Hudlicky

Brock University

Department of Chemistry and Centre for Biotechnology

500 Glenridge Avenue

St. Catharines, Ontario L2S 3A1

Canada

Anushree Kamath

State University of New York

Department of Chemistry and

Institute of Chemical Biology & Drug Discovery

Stony Brook, NY 11794-3400

USA

Chaitan Khosla

Stanford University

Departments of Chemistry, Chemical Engineering, and Biochemistry

380 Roth Way

Stanford, CA 94305

USA

Jason G. Lewis

Ardelyx

34175 Ardenwood Blvd., Suite 100

Fremont, CA 94555

USA

Brian A. Loy

Stanford University

Departments of Chemistry and Chemical and Systems Biology

Stanford, CA 94305

USA

Vincent Mascitti

Pfizer Global R&D

Groton Laboratories

Easter Point Road

Groton, CT 06340

USA

Aaron E. May

Stanford University

Departments of Chemistry, Chemical Engineering, and Biochemistry

380 Roth Way

Stanford, CA 94305

USA

Katherine E. Near

Stanford University

Departments of Chemistry and Chemical and Systems Biology

337 Campus Dr

Stanford, CA 94305

USA

David J. Newman

DCTD and FNLCR

Natural Products Branch

Developmental Therapeutics Program

Frederick, MD 21702

USA

Hardwin O'Dowd

Vertex Pharmaceuticals

130 Waverly Street

Cambridge, MA 02139

USA

Iwao Ojima

State University of New York

Department of Chemistry and Institute of Chemical Biology & Drug Discovery

Stony Brook, NY 11794-3400

USA

Stefano Rizzo

Max Planck Institute of Molecular Physiology

Department of Chemical Biology

Otto-Hahn-Str. 11

44227 Dortmund

Germany

Ralph P. Robinson

Pfizer Global R&D

Groton Laboratories

Easter Point Road

Groton, CT 06340

USA

Dieter Schinzer

Otto-von-Guericke Universität Magdeburg

Chemisches Institut

Lehrstuhl für Organische Chemie

Universitätsplatz 2

39106 Magdeburg

Germany

Joshua D. Seitz

State University of New York

Department of Chemistry and Institute of Chemical Biology & Drug Discovery

Stony Brook, NY 11794-3400

USA

Punit P. Seth

Isis Pharmaceuticals

Department of Medicinal Chemistry

2855 Gazelle Court

Carlsbad, CA 92010

USA

Daryl Staveness

Stanford University

Departments of Chemistry and Chemical and Systems Biology

337 Campus Dr

Stanford, CA 94305

USA

Keisuke Suzuki

Tokyo Institute of Technology

Department of Chemistry

2-12-1, O-okayama

Meguro-ku, Tokyo 152-8551

Japan

Eric E. Swayze

Isis Pharmaceuticals

2855 Gazelle Court

Carlsbad, CA 92010

USA

Eric Therrien

Molecular Forecaster Inc.

969 Marc-Aurele Fortin

Laval, Quebec H7L 6H9

Canada

Vimal Varghese

Brock University

Department of Chemistry and

Centre for Biotechnology

500 Glenridge Avenue

St. Catharines, Ontario L2S 3A1

Canada

Vijay Wakchaure

Max Planck Institute of Molecular Physiology

Department of Chemical Biology

Otto-Hahn-Str. 11

44227 Dortmund

Germany

Herbert Waldmann

Max Planck Institute of Molecular Physiology

Department of Chemical Biology

Otto-Hahn-Str. 11

44227 Dortmund

Germany

Paul A. Wender

Stanford University

Departments of Chemistry and Chemical and Systems Biology

337 Campus Dr

Stanford, CA 94305

USA

Kai Xi

Purdue University

Department of Chemistry and

Department of Medicinal Chemistry

560 Oval Drive

West Lafayette, IN 47907-2084

USA

Yoshizumi Yasui

Kanagawa University of Human Services

Faculty of Health and Social Work

1-10-1, Heiseicho

Yokosuka, Kanagawa 238-8522

Japan

Preface

The Ebers Papyrus, originating from about 1500 BC, is one of the oldest documents that describe the use of natural products for healing diseases. Several herbs are described in its about 700 remedies and magical formulas, for example, the squill (Urginea maritima) against dropsy (edema caused by cardiac insufficiency). Indeed, this plant contains cardiac glycosides that are beneficial in such a condition. Another important document, from the first century AD, is the book De Materia Medica of the Greek physician Dioscurides. It lists about 600 medicinal plants, 35 animal products, and 90 minerals. Obviously, these collections of remedies resulted from the accumulated experience of earlier millennia. Not all contained information is reliable; in later centuries, the wheat had to be separated from the chaff, a task that still today is not completely accomplished if we consider so many marketed herbal preparations without proven therapeutic value. On the other hand, opium, the fever-lowering bark of the Cinchona tree, the foxglove (Digitalis purpurea), and many other herbal drugs remained in therapy, later being replaced by the isolated active principles morphine, quinine, digitoxin, and others.

The main sources of drugs from nature or lead structures for such drugs are plants, microorganisms, animals, and humans. Plants provide drugs and lead structures for the treatment of a large variety of different diseases. Microorganisms yield mainly antibiotics but also other therapeutic principles, for example, the important statins. Animal toxins almost exclusively serve as pharmacological tools, but human neurotransmitters and hormones were, and still are, valuable leads for more potent and selective analogs, sometimes even with inverse pharmacological activities. The main advantage of many natural products is their three-dimensional structure, avoiding the “flatness” of so many synthetic compounds, and their high degree of chemical diversity, going far beyond the creativity of organic chemists. However, this is also their main disadvantage, besides the problems of accessibility (consider the early problems in taxol supply); due to the complexity of their structures, chemical variation is often so difficult and costly that pharma companies hesitate to invest in their optimization. On the other hand, natural products, whether resulting from plants or from microorganisms, are excellent lead structures, from the viewpoint of ligand–target interactions. In their biosynthesis, all plant secondary metabolites have already “seen” the binding site of a protein; thus, their structural features and properties mediate the interaction with proteins. In addition, many of these compounds serve a certain purpose; they protect a plant that cannot run away in sight of a predator, because they are bitter, sharp, or slightly toxic (only bad experience trains the predator to avoid a certain plant – a dead animal cannot learn anymore!). Correspondingly, in evolution, the plants producing such compounds had a better chance to survive and to reproduce. Microorganisms need antibiotics to compete with other microorganisms. Last but not least, animal and human active principles are perfect lead structures because they act at endogenous receptors and other therapeutically relevant targets.

There are already numerous books on the role of natural products in drug research – therefore, why present another one? The simple reason is that natural products were not only important in the past. Taxol, the statins, artemisinin, and epothilone are just a few examples of natural products that recently yielded important and successful new drugs and many more are under active investigation. A recent publication analyzed the origin of 1073 new chemical entities (small molecules, excluding biologicals) of the years 1981–2010 [1]: 6% of these drugs were natural products themselves, 28% were derivatives of natural products, 14% were characterized as mimics of natural products, and 16% as synthetics whose pharmacophore was derived from a natural product. In total, almost 2/3 of the newly introduced drugs originated in some manner from a natural product! This predominance of natural products is even more pronounced in the area of anticancer drugs and in the field of antibiotics.

We are very grateful to Stephen Hanessian, a world-leading expert in the field of natural product chemistry, for undertaking the task to edit this book with so many chapters on recent developments and success stories. In addition, we are grateful to all chapter authors for their excellent work, which provides a comprehensive overview of current research on new drugs from natural products. Finally, we would like to thank Frank Weinreich and Heike Nöthe of Wiley-VCH Verlag GmbH for their ongoing commitment to our book series Methods and Principles in Medicinal Chemistry.

October 2013Düsseldorf, GermanyRaimund MannholdWeisenheim am Sand, GermanyHugo KubinyiZürich, SwitzerlandGerd Folkers

Reference

1. Newman, D.J. and Cragg, G.M. (2012) Natural products as sources of new drugs over the 30 years from 1981 to 2010. Journal of Natural Products, 75, 311–335.

Personal Foreword

Nature has been an abundant source of bioactive compounds for millennia. Modern science has unraveled the complex molecular architectures of natural products often possessing an unusual assortment of functional groups that would have defied all odds only a few decades ago.

Nature has also been the provider, the enticer, and the healer. Indeed, some of the most impressive contributions to the field of organic chemistry have been associated with the design and total synthesis of natural products. The same could be said of their biological activities, mode of action, and therapeutic value. These major advances at the interface between the chemistry and biology of natural products have showcased the courage, resolve, and, above all, the passion of dedicated scientists.

As the title itself reflects, this book is dedicated to the importance of natural products in medicinal chemistry. Structured into five thematic parts, the book consists of 16 chapters, each contributed by experts in the field, who have admirably written about their seminal contributions over the years to address diverse aspects of natural products in chemistry and biology. The five themes cover principally the importance of natural products as drugs, platforms for both chemical and genetic modifications to create newer entities, unique collections of biogenetically diverse compounds, and inspiration points for the design and synthesis of surrogates, mimics, hybrids, and chimeras.

I thank all the contributors for their efforts and collegiality in making this a very special volume that will be pedagogically and practically informative to students and professionals alike.

October 16, 2013

Stephen Hanessian

Part One

Natural Products as Sources of Potential Drugs and Systematic Compound Collections

1

Natural Products as Drugs and Leads to Drugs: An Introduction and Perspective as of the End of 20121

David J. Newman and Gordon M. Cragg

1.1 Introduction

Two very frequent comments (together or separately) that have been made, in writing and verbally, over the last 15–20 years can be summarized as follows:

The use (or pursuit) of natural products as either drugs or as leads to new chemistry that will lead to drugs is now passé, and that what is needed is the use of very high-throughput screens, coupled to large numbers of novel molecules produced by combinatorial chemistry.The clever use of computational methods to fit compounds into the active sites of the enzyme (or receptor) of interest will permit the derivation of large numbers of drugs to be discovered and then commercialized rapidly as a result.

We think that perhaps the best answer to comments such as these can be seen in two simple graphical models shown in Figures 1.1 and 1.2. In Figure 1.1, we have plotted the number of small ie meaning up to roughly 45 amino acid residues, with Byetta® being the upper limit, against the number of “N” and “S*” classifications as defined in Ref. [1] from January 1, 1981 through December 31, 2012. In Figure 1.2, we have taken the total number of “N-related” approved drugs over the same time frame as a percentage of the approved drugs for that year. The mean percentage per year of “N-derived drugs” ± the standard deviation over this time frame is 33.4 ± 8.9%, and in 2010, 50% of the 18 approved small-molecule drugs were in this category.

Figure 1.1 Numbers of natural product-related (N plus S*) small molecules per year (1981–2012).

Figure 1.2 Percentage of natural product related (N) small molecules per year (1981–2012).

What must be borne in mind is that these are the most conservative figures as we only count a drug once, in the United States if it was first approved by the FDA (Food and Drug Administration) or the approving country's equivalent of the FDA. Thus, compounds that are subsequently approved for another disease either in the same or in a different country, or whose pharmaceutical properties are extended by slow release or by combination with other agents, are not counted again. There are a few exceptions to this general rule such as the use of nanoparticle-associated albumins in the case of some versions of Taxol® and combinations of different modified insulins, but these, however, account for less than 0.3% of about 1500 compounds (small and large) approved in the last 32 years.

In Figure 1.3, we have shown the breakdown by category, again using the classifications used previously [1] of all drugs and small drugs approved over the last 32 years from January 1, 1981 through December 31, 2012, which should be studied by the interested reader. Again, if one looks at these diagrams, the role of natural product structures as leads (N- and S*-linked materials) is still very significant and even in 2011–2012, 41 of the 62 small-molecule drugs fell into these categories (data not shown but available from the authors on request).

Figure 1.3 Sources of all approved drugs 1981–2012.

In addition, in Figure 1.4, as befits authors from the US National Cancer Institute (NCI), we have shown the breakdown for all antitumor drugs from the beginning of chemotherapy treatments in the mid-1930s, using variations on the mustard gas used in warfare in World War I, through to the large number of tyrosine protein kinase inhibitors approved in the last few years, with almost all being isosteres of ATP and binding at the ATP site. As already mentioned, in the 2011–2012 N to S* breakdown, 16 of the 18 small-molecule antitumor drugs fell into these classifications. The isostere link was reconfirmed by an excellent presentation given by Fabbro [2] of Novartis at the recent NAD 2012 Meeting in Olomouc, the Czech Republic in July 2012. Finally in this section, the influence of natural product structures on antitumor agents is such that if one sums the “N-related” then the answer is 89 or 47%, with the “S*-related” equaling 38 or 20% overall. Thus, one can see that natural product-related compounds in this disease category equal 67% of all approved small-molecule drug entities in this time frame. Although not shown, comparable figures are also seen for anti-infective agents over the 32-year time frame covered by (we have not gone back to the late 1930s for these data, but may well do so in time).