Handbook of Marine Natural Products Ernesto Fattorusso William H

Handbook of Marine Natural Products Ernesto Fattorusso William H. Gerwick Orazio Taglialatela-Scafati Editors

Handbook of Marine Natural Products

With 691 Figures and 45 Tables Editors Ernesto Fattorusso Dipartimento di Chimica delle Sostanze Naturali Universita` di Napoli Federico II Via Montesano 49 80131 Naples Italy

William H. Gerwick Scripps Institution of Oceanography Skaggs School of Pharmacy and Pharmaceutical Sciences University of California San Diego, CA 92093 USA

Orazio Taglialatela-Scafati Dipartimento di Chimica delle Sostanze Naturali Universita` di Napoli Federico II Via Montesano 49 80131 Naples Italy

ISBN: 978-90-481-3833-3 This publication is available also as: Electronic publication under ISBN 978-90-481-3834-0 and Print and electronic bundle under ISBN 978-90-481-3856-2 DOI: 10.1007/978-90-481-3834-0 Springer Dordrecht, Heidelberg, New York, London

Library of Congress Control Number: 2012934368

# Springer ScienceþBusiness Media B.V. 2012

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Springer is part of Springer ScienceþBusiness Media (www.springer.com) Preface

The field of marine natural products is nearing the 50 year mark since its origin in the 1960s with pioneering studies in JapanbyToshiIrieandintheUnitedStates by Paul Scheuer. Since that time and their early studies to describe the fundamental organic chemistry of marine organisms, it has grown and evolved to be highly multidisciplinary, integrating methods development in organic structure analysis, pharmacology, synthetic and medicinal chemistry, toxicology, biosynthesis and mechanistic bioorganic chemistry,andgenomics.Indeed,thefieldis reaching a maturity in approach and societal significance that could only be guessed at in the early days, and several marine-derived or marine-inspired drugs are now on the market (7) or in various stages of clinical trial (13). Of equal significance, more than 120 marine natural products are articles of com- merce for their utility as reference standards and pharmacological probes of cell biology. However, with this maturity comes a responsibility on the part of students and researchers in the marine natural products sciences to know the history and origins of the field, and so enabled, to keep vital and current the subject through innovation and creative new science. A number of reviews and multi-author monographs have appeared in this field with the primary objective of providing a scholarly perspective on some dimen- sion of marine natural products as well as an entry point to the relevant literature. Most notably, the book series championed by Paul Scheuer and the yearly scholarly reviews by Faulkner and subsequently by the Munro and Blunt team have served our community well in these regards. However, except for early texts by Scheuer and Pietra, and various specialty volumes such as that of Valerie Paul on Marine Chemical Ecology, comprehensive textbooks covering this field have not appeared which are suitable as an introduction to the field or a companion to an advanced undergraduate/graduate university course on the topic. This has been a shortcoming which has both made teaching of this subject difficult in the classroom and complex to articulate the scope and nature to those outside of the field. It is with this goal and vision in mind that the editors first came together in 2008 at a Marine Natural Products Gordon Research Conference in Ventura, California, to begin organizing a textbook in this field of marine natural products science. At that time we outlined a volume of considerable scope, divided into six sections, which would provide a comprehensive overview of this highly diverse field.

v vi Preface

We next identified potential leaders in the field to provide chapters on specific topics within each of these sections. We were highly gratified that almost all contacted authors were able to accept our invitation to contribute to this handbook, and, subsequently, to receive their inspiring and scholarly chapters. Without the efforts and dedication of these many authors, this volume clearly would not have been possible, and we thank them all most sincerely. We believe that it was the shared vision of all of the authors that provided the motivation to contribute to a textbook that would help define the field as well as provide a contemporary guide to those entering this exciting branch of science. A unique feature of this volume is the inclusion of a series of thought- provoking study questions at the end of each chapter. Some of these will aid in understanding the principles and concepts presented in each chapter, whereas others represent actual topics for further research. A careful consideration of these questions by interested students will certainly enhance the level of understanding of the material presented as well as stimulate new ideas suitable as actual research projects. Upon receipt of the various chapters the editors undertook the multistage process of editing, improving consistency between chapters, and identifying index terms. We thank the multitude of people at our respective institutions for their contributions to various aspects of this lengthy process. We also thank the several key people at Springer who have helped this volume become a reality. And finally, we thank our families for their understanding during the many early mornings and late evenings that we were engaged in the writing and editorial process. However, if we reach our vision to have provided a truly useful text for those entering the field of marine natural products science, then, indeed, it will all have been worthwhile. To the readers of this volume, we sincerely wish that you will find knowledge, perspective, and inspiration in your scholarly pursuit of the marine natural products sciences. We hope that this volume will assist you as you continue the tradition of innovation and creativity that has characterized this field over its first 50 years.

Ernesto Fattorusso William H. Gerwick Orazio Taglialatela-Scafati February 2012 About the Editors

Ernesto Fattorusso Dipartimento di Chimica delle Sostanze Naturali Universita` di Napoli Federico II Via Montesano 49 80131 Naples Italy

Ernesto Fattorusso graduated in Chemistry in 1960 and got Libera Docenza in Natural Products Chemistry in 1967. He was assistant professor at the University of Naples (1963–1975); in 1975, he became full Professor of Organic Chemistry at the Faculty of Science. In 1980, he moved to the Faculty of Pharmacy, where he was elected Dean twice. Since 2011, he is Professor Emeritus of Organic Chemistry of the University of Naples Federico II. He has published more than 400 scientiﬁc papers and on 2008 edited the book Modern Alkaloids. His research activity started by studying the structure and biogenesis of melanins, and, since the end of 1960s, he has pioneered the chemical investigation of marine metabolites. He has won the A. Quilico Award (2002) of Italian Chemical Society, the P. Scheuer Award (2004) of Akademie of Erfurt, and the P. Scheuer Award (2010) of University of Honolulu Foundation. Since 2005, he is Editor of Steroids.

vii viii About the Editors

William H. Gerwick Scripps Institution of Oceanography Skaggs School of Pharmacy and Pharmaceutical Sciences University of California San Diego, CA 92093 USA

William Gerwick holds a Ph.D. from Scripps Institution of Oceanography, University of California San Diego (1981) where he described the unique organic secondary metabolites of several marine macroalgae. His postdoctoral research focused on the biosynthesis of microbial natural products at the University of Connecticut. He was an assistant professor of Chemistry at the University of Puerto Rico in 1982–1983, and then professor of Pharmaceutical Sciences at the Oregon State University College of Pharmacy for over 20 years. In 2005, he returned as Full Professor to Scripps and the newly formed Skaggs School of Pharmacy and Pharmaceutical Sciences, UCSD, and in 2011 was named Distin- guished Professor of Oceanography and Pharmaceutical Sciences. He has served as president of the American Society of Pharmacognosy, a member for the NIH scientific review committee on natural products chemistry, and holds affiliate positions at several other universities and institutions around the world. In 2011, he was awarded the UC San Diego Chancellor’s Associates Award for Excellence in Engineering and Scientific Research. He has served on several scientific and review panels in the USA and abroad, including his current role on the Oceans and Human Health National Advisory Committee. His research fuses marine natural products drug discovery research with biosynthetic investigations at the chemical, biochemical, and genetic levels, and he has pioneered the integrated use of advanced analytical instrumentation in this area of scientific research. About the Editors ix

Orazio Taglialatela-Scafati Dipartimento di Chimica delle Sostanze Naturali Universita` di Napoli Federico II Via Montesano 49 80131 Naples Italy

Orazio Taglialatela-Scafati holds a Ph.D. in Bioactive Natural Products (1997) from the University of Naples Federico II. He was appointed as Assistant Professor of Organic Chemistry in 1999 and, since 2004, he is Associate Professor in Organic Chemistry at Faculty of Pharmacy, University of Naples Federico II. He has served on several scientific and review panels and he is member of the Editorial Board of the scientific journals Steroids and Marine Drugs. His research activity focuses on isolation, stereostructural elucidation, and semi-synthetic trans- formation of bioactive secondary metabolites (especially with antitumor, antima- larial, and anti-inflammatory activities) from marine invertebrates and terrestrial plants. He is the author of about 100 research papers and the editor of the books Flavour and Fragrance Chemistry and Modern Alkaloids. Contents

VOLUME 1

Part 1 Natural Product Trends in Different Groups of Marine Life ...... 1

1 Taxonomy and Marine Natural Products Research ...... 3 John Blunt, John Buckingham, and Murray Munro 2 The Chemistry of Marine Algae and Cyanobacteria ...... 55 Hyukjae Choi, Alban R. Pereira, and William H. Gerwick 3 The Chemistry of Marine Bacteria ...... 153 Brian T. Murphy, Paul R. Jensen, and William Fenical 4 The Chemistry of Marine Sponges ...... 191 Sherif S. Ebada and Peter Proksch 5 The Chemistry of Marine Tunicates ...... 295 Marialuisa Menna and Anna Aiello

Part 2 Structure Elucidation of Marine Natural Products ...... 387

6 The Role of Databases in Marine Natural Products Research . . . 389 John Blunt, Murray Munro, and Meg Upjohn 7 Contemporary Strategies in Natural Products Structure Elucidation ...... 423 Jaime Rodrı´guez, Phillip Crews, and Marcel Jaspars 8 Strategies for Structural Assignment of Marine Natural Products Through Advanced NMR-based Techniques ...... 519 Alfonso Mangoni 9 NMR Methods for Stereochemical Assignments ...... 547 Kirk R. Gustafson

xi xii Contents

10 Quantum Chemical Calculation of Chemical Shifts in the Stereochemical Determination of Organic Compounds: A Practical Approach ...... 571 Simone Di Micco, Maria Giovanna Chini, Raffaele Riccio, and Giuseppe Bifulco 11 Marine Natural Products Synthesis ...... 601 Victoria L. Wilde, Jonathan C. Morris, and Andrew J. Phillips

VOLUME 2

Part 3 Marine Natural Products and Chemical Ecology ...... 675

12 Antipredatory Defensive Roles of Natural Products from Marine Invertebrates ...... 677 Joseph R. Pawlik 13 Antipredatory Defensive Role of Planktonic Marine Natural Products ...... 711 Adrianna Ianora, Antonio Miralto, and Giovanna Romano 14 Antifouling Activity of Marine Natural Products ...... 749 Pei-Yuan Qian and Sharon Ying Xu 15 Chemically Mediated Competition and Host–Pathogen Interactions Among Marine Organisms ...... 823 Marc Slattery and Deborah J. Gochfeld 16 Marine Metabolites and Metal Ion Chelation ...... 861 Stephen H. Wright, Andrea Raab, Jo¨rg Feldmann, Eva Krupp, and Marcel Jaspars

Part 4 Biosynthesis of Marine Natural Products ...... 893

17 Biosynthetic Studies Through Feeding Experiments in Marine Organisms ...... 895 Angelo Fontana, Emiliano Manzo, M. Letizia Ciavatta, Adele Cutignano, Margherita Gavagnin, and Guido Cimino 18 Biosynthetic Principles in Marine Natural Product Systems ...... 947 David H. Sherman, Christopher M. Rath, Jon Mortison, Jamie B. Scaglione, and Jeffrey D. Kittendorf 19 Mechanisms of Halogenation of Marine Secondary Metabolites ...... 977 Claudia Wagner and Gabriele M. Ko¨nig Contents xiii

Part 5 Biomedical Potential of Marine Natural Products ...... 1025

20 Marine Natural Products That Target Microtubules ...... 1027 Raymond J. Andersen, Dehai Li, Matt Nodwell, Michel Roberge, Wendy Strangman, and David E. Williams 21 Marine Natural Products Active Against Protozoan Parasites ...... 1075 Ernesto Fattorusso and Orazio Taglialatela-Scafati 22 Mechanism-based Screening for Cancer Therapeutics with Examples from the Discovery of Marine Natural Product-based HIF-1 Inhibitors ...... 1111 Dale G. Nagle and Yu-Dong Zhou 23 Enzyme Inhibitors from Marine Invertebrates ...... 1145 Yoichi Nakao and Nobuhiro Fusetani 24 Fluorescent Proteins from the Oceans: Marine Macromolecules as Advanced Imaging Tools for Biomedical Research ...... 1231 Edward G. Smith, Cecilia D’Angelo, Franz Oswald, G. Ulrich Nienhaus, and J. Wiedenmann 25 From Biosilica of Sponges (Demospongiae and Hexactinellida) to Fabricated Biomedical Materials ...... 1259 Xiaohong Wang, Heinz C. Schro¨der, Matthias Wiens, Lu Gan, Wolfgang Tremel, and Werner E. G. Muller€ 26 Meeting the Supply Needs of Marine Natural Products ...... 1285 David J. Newman and Gordon M. Cragg 27 Legal and Ethical Issues Involving Marine Biodiscovery and Development ...... 1315 Gordon M. Cragg, Flora Katz, David J. Newman, and Joshua Rosenthal

Part 6 Marine Toxins: A Problem for Public Health and Seafood Resources ...... 1343

28 Seafood Toxins: Classes, Sources, and Toxicology ...... 1345 Patrizia Ciminiello, Martino Forino, and Carmela Dell’Aversano 29 Marine Protein Toxins ...... 1389 Hiroshi Nagai 30 Marine Natural Products into the Future ...... 1421 William H. Gerwick Index ...... 1429 List of Contributors

Anna Aiello Dipartimento di Chimica delle Sostanze Naturali, Universita` degli Studi di Napoli “Federico II”, Naples, Italy Raymond J. Andersen Departments of Chemistry and Earth & Ocean Sciences, University of British Columbia, Vancouver, BC, Canada Giuseppe Bifulco Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Fisciano (Salerno), Italy John Blunt Department of Chemistry, University of Canterbury, Christchurch, New Zealand John Buckingham Dictionary of Natural Products, CRC Press/Informa, London, UK Maria Giovanna Chini Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Fisciano (Salerno), Italy Hyukjae Choi Scripps Institution of Oceanography, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA, USA M. Letizia Ciavatta Istituto di Chimica Biomolecolare – Consiglio Nazionale delle Ricerche, Pozzuoli (Naples), Italy Patrizia Ciminiello Dipartimento di Chimica delle Sostanze Naturali, Universita` degli Studi di Napoli “Federico II”, Naples, Italy Guido Cimino Istituto di Chimica Biomolecolare – Consiglio Nazionale delle Ricerche, Pozzuoli (Naples), Italy Gordon M. Cragg Natural Products Branch, Developmental Therapeutics Program, National Cancer Institute, NCI-Frederick, Frederick, MD, USA Phillip Crews Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA, USA Adele Cutignano Istituto di Chimica Biomolecolare – Consiglio Nazionale delle Ricerche, Pozzuoli (Naples), Italy

xv xvi List of Contributors

Cecilia D’Angelo National Oceanography Centre Southampton, University of Southampton, Southampton, UK Carmela Dell’Aversano Dipartimento di Chimica delle Sostanze Naturali, Universita` degli Studi di Napoli “Federico II”, Naples, Italy Simone Di Micco Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Fisciano (Salerno), Italy Sherif S. Ebada Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine University, Duesseldorf, Germany; Department of Pharmacognosy and Phytochemistry, Faculty of Pharmacy, Ain-Shams University, Cairo, Egypt Ernesto Fattorusso Dipartimento di Chimica delle Sostanze Naturali, Universita` di Napoli Federico II, Naples, Italy Jo¨rg Feldmann Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Old Aberdeen, Scotland, UK William Fenical Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, CA, USA Angelo Fontana Istituto di Chimica Biomolecolare – Consiglio Nazionale delle Ricerche, Pozzuoli (Naples), Italy Martino Forino Dipartimento di Chimica delle Sostanze Naturali, Universita` degli Studi di Napoli “Federico II”, Naples, Italy Nobuhiro Fusetani Fisheries and Oceans Hakodate, Graduate School of Fisheries Sciences, Hokkaido University, 3-1-1, Minato-cho, Hakodate, Japan Lu Gan National Research Center for Geoanalysis, Beijing, China Margherita Gavagnin Istituto di Chimica Biomolecolare – Consiglio Nazionale delle Ricerche, Pozzuoli (Naples), Italy William H. Gerwick Scripps Institution of Oceanography, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA, USA Deborah J. Gochfeld National Center for Natural Products Research, The University of Mississippi, Oxford, MS, USA Kirk R. Gustafson Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD, USA Adrianna Ianora Functional and Evolutionary Ecology, Laboratory Stazione Zoologica Anton Dohrn, Naples, Italy Marcel Jaspars Department of Chemistry, Marine Biodiscovery Centre, University of Aberdeen, Aberdeen, UK List of Contributors xvii

Paul R. Jensen Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, CA, USA Flora Katz John E. Fogarty International Center, National Institutes of Health, Bethesda, MD, USA Jeffrey D. Kittendorf Life Sciences Institute and Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA Gabriele M. Ko¨nig Institute for Pharmaceutical Biology, University of Bonn, Bonn, Germany Eva Krupp Department of Chemistry, Marine Biodiscovery Centre, University of Aberdeen, Old Aberdeen, Scotland, UK Dehai Li Departments of Chemistry and Earth & Ocean Sciences, University of British Columbia, Vancouver, BC, Canada Alfonso Mangoni Dipartimento di Chimica delle Sostanze Naturali, Universita` di Napoli Federico II, Naples, Italy Emiliano Manzo Istituto di Chimica Biomolecolare – Consiglio Nazionale delle Ricerche, Pozzuoli (Naples), Italy Marialuisa Menna Dipartimento di Chimica delle Sostanze Naturali, Universita` degli Studi di Napoli “Federico II”, Naples, Italy Antonio Miralto Functional and Evolutionary Ecology Laboratory, Stazione Zoologica Anton Dohrn, Naples, Italy Jonathan C. Morris School of Chemistry, University of New South Wales, Sydney, Australia Jon Mortison Life Sciences Institute and Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA Werner E. G. Muller€ Institute for Physiological Chemistry, Medical Center of the Johannes Gutenberg University, Mainz, Germany Murray Munro Department of Chemistry, University of Canterbury, Christchurch, New Zealand Brian T. Murphy Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, CA, USA Hiroshi Nagai Department of Ocean Science, Tokyo University of Marine Science and Technology, Minato-ku, Tokyo, Japan Dale G. Nagle Department of Pharmacognosy, School of Pharmacy, The University of Mississippi, Oxford, MS, USA xviii List of Contributors

Yoichi Nakao School of Advanced Sciences and Technologies, Waseda University, 3-4-1, Shinjuku-ku, Tokyo, Japan David J. Newman Natural Products Branch, Developmental Therapeutics Program, National Cancer Institute, NCI-Frederick, Frederick, MD, USA G. Ulrich Nienhaus Center for Functional Nanostructures, Karlsruhe Institute of Technology, Karlsruhe, Germany; Department of Physics, University of Illinois at Urbana-Champaign, Urbana, IL, USA Matt Nodwell Departments of Chemistry and Earth & Ocean Sciences, Univer- sity of British Columbia, Vancouver, BC, Canada Franz Oswald Department of Internal Medicine I, University of Ulm, Ulm, Germany Joseph R. Pawlik Department of Biology and Marine Biology, Center for Marine Science, University of North Carolina Wilmington, Wilmington, NC, USA Alban R. Pereira Scripps Institution of Oceanography, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA, USA Andrew J. Phillips Department of Chemistry, Yale University, New Haven, CT, USA Peter Proksch Institute of Pharmaceutical Biology and Biotechnology, Heinrich- Heine University, Duesseldorf, Germany Pei-Yuan Qian KAUST Global Collaborative Program, Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China Andrea Raab Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Old Aberdeen, Scotland, UK Christopher M. Rath Life Sciences Institute and Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA Raffaele Riccio Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Fisciano (Salerno), Italy Michel Roberge Department of Biochemistry & Molecular Biology, University of British Columbia, Vancouver, BC, Canada Jaime Rodrı´guez Departamento de Quı´mica Fundamental, Campus da Zapateira. Universidade da Corun˜a, A Corun˜a, Spain Giovanna Romano Functional and Evolutionary Ecology, Laboratory Stazione Zoologica Anton Dohrn, Naples, Italy List of Contributors xix

Joshua Rosenthal John E. Fogarty International Center, National Institutes of Health, Bethesda, MD, USA Jamie B. Scaglione Life Sciences Institute and Department of Medicinal Chem- istry, University of Michigan, Ann Arbor, MI, USA Heinz C. Schro¨der Institute for Physiological Chemistry, Medical Center of the Johannes Gutenberg University, Mainz, Germany David H. Sherman Life Sciences Institute and Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA Marc Slattery Department of Pharmacognosy, The University of Mississippi, Oxford, MS, USA; National Center for Natural Products Research, The University of Mississippi, Oxford, MS, USA Edward G. Smith National Oceanography Centre Southampton, University of Southampton, Southampton, UK Wendy Strangman Departments of Chemistry and Earth & Ocean Sciences, University of British Columbia, Vancouver, BC, Canada Orazio Taglialatela-Scafati Dipartimento di Chimica delle Sostanze Naturali, Universita` di Napoli Federico II, Naples, Italy Wolfgang Tremel Institute for Chemistry, Johannes Gutenberg University Mainz, Mainz, Germany Meg Upjohn Physical Sciences Library, University of Canterbury, Christchurch, New Zealand Claudia Wagner Institute for Pharmaceutical Biology, University of Bonn, Bonn, Germany Xiaohong Wang National Research Center for Geoanalysis, Beijing, China; Institute for Physiological Chemistry, Medical Center of the Johannes Gutenberg University, Mainz, Germany J. Wiedenmann National Oceanography Centre Southampton, University of Southampton, Southampton, UK Matthias Wiens Institute for Physiological Chemistry, Medical Center of the Johannes Gutenberg University, Mainz, Germany Victoria L. Wilde Department of Chemistry, Yale University, New Haven, CT, USA David E. Williams Departments of Chemistry and Earth & Ocean Sciences, University of British Columbia, Vancouver, BC, Canada xx List of Contributors

Stephen H. Wright Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Old Aberdeen, Scotland, UK Sharon Ying Xu KAUST Global Collaborative Program, Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China Yu-Dong Zhou Department of Pharmacognosy, School of Pharmacy, The University of Mississippi, Oxford, MS, USA Introduction

Ernesto Fattorusso, Willam H. Gerwick, and Orazio Taglialatela-Scafati

The use of both terrestrial and marine natural products (MNPs) as treatments for different ailments has accompanied humanity from its earliest civilizations. Nature represents an endless arsenal of new bioactive compounds and the study of these metabolites has historically proven to be of immense benefit in the drug discovery process. The chemical investigation of terrestrial natural products can be dated back to the beginning of the nineteenth century, when organic molecules started to be studied with scientific rigour. Much younger is the chemical investigation of marine natural products (MNPs), now about 65 years old. Although approximately 70% of the earth’s biosphere is made up by oceans, a unique environment that hosts a wealth of plants, animals, and microorganisms, a variety of reasons have ham- pered the development of MNP chemistry in the nineteenth and at the beginning of twentieth century. These are mainly related to technical constraints resulting from difficulties in the collection of marine organisms from the sea and, related to this, the relatively small amount of organisms that could be collected. As a result, this situation inevitably resulted in a very limited quantity of metabolites obtained from the extraction and purification processes. Due to impressive progress in collection techniques (with the introduction of SCUBA), purification, and, above all, in structural studies through improvements in spectroscopic technologies, the last 40 years have witnessed an explosion of research focused on the immense biodiversity of the marine environment. This has resulted in a multidisciplinary endeavor involving natural product chemists, marine ecologists, pharmacologists and biochemists. The number of novel MNPs discovered to date has been recently estimated to be about 30,000, and their incredible diversity can be well appreciated by consulting the precious reviews published by the late D. J. Faulkner in Natural Products Reports, a series now continued by Blunt, Munro, and others. These annual reviews report all the new marine natural products emerging in the scientific literature and also give a fine idea of the relative prolificacy of the different organisms. Marine invertebrates (sponges, tunicates, soft corals, gorgonians, molluscs, echinoderms) are by far the most prolific producers of secondary metabolites, compared to fish and other vertebrates. This observation can have at least two possible explanations: (1) Their sessile and soft-bodied forms, combined with their consequent lack of mechanical or morpho- logical weapons to be used as protection, force them to rely largely on a chemical

xxi xxii Introduction arsenal to deter predation from other reef organisms. Since the production of secondary metabolites has been selected by these organisms as a strategy for their survival, the greater is the number of secondary metabolites produced by an organism the greater are its chances in winning the evolutionary competition. (2) These marine invertebrates harbor in their tissue, in extra- and intracellular spaces, a great number of symbiotic and associated microorganisms and, thus, their biosynthetic potential is indirectly increased by the contribution of the biosynthetic machinery of the different symbiotic cells. Thus, it is not surprising that one of the most recent trends in MNP chemistry, the direct chemical investigation of marine microbes (e.g., bacteria collected in the sediments and cyanobacteria), has revealed an incredible richness of interesting secondary metabolites. Moreover, some classes of marine microorganisms are actually responsible for the production of the toxic metabolites found in marine invertebrates, and several have been demonstrated to cause human intoxications of various levels of seriousness. The study of marine toxins was initiated at the very beginning of the MNP era, reaching milestones such as the isolation and structure elucidation of maitotoxin, the largest nonproteinaceous toxin known to date, and characterized by a skeleton of 164 carbon atoms. With this wealth and variety of topics in mind, we decided to structure the present handbook with the aim of representing the different aspects of MNP science (i.e., ecology and pharmacology of bioactive compounds; recent advances in isolation, biosynthesis, and structural elucidation) in a volume which should provide representative examples of recent results as well as of the future outlook of this multidisciplinary branch of science. Obviously, this handbook is not intended as a comprehensive coverage of the entire field of MNP research, but we feel that through the diversity of topics treated, it can provide a good idea of its variety and richness. Thus, this handbook should be useful to a mixture of scientists and students in academia as well as industry that are interested in the most recent developments in this area. In addition, we have asked the authors to present their topics in a clear and didactic way, making a frequent use of examples and connec- tions to their practical utility. Thus, we believe that this handbook will also serve as an excellent textbook for Ph.D. and postdoctoral students in several courses within the marine sciences. The study questions included at the end of each chapter are intended to be thought provoking stimuli to further deepen student knowledge and interest in the subject matter. The handbook includes 30 chapters grouped into six sections. Section I provides an overall idea of the production and diversity of MNPs within some representative groups of marine organisms. Of course, the five chapters in this section do not aim at reporting all of the molecules isolated from each group, but rather, they describe the characteristics as well as unique carbon and heterocyclic skeletons and assorted functional groups. The astounding variety (and often complexity) of the chemical structures of MNP poses challenging problems to the chemists engaged in their stereostructural elucidation, which is also made more difficult by the small amounts commonly obtained from natural sources. In Sect. II, the reader will find described different aspects of the structural elucidation process with special attention given to Introduction xxiii

NMR spectroscopy. Recent advancements in NMR spectroscopy have allowed modern MNP laboratories to routinely solve structures on submicrogram quantities, and have undoubtedly fostered the recent explosion of novel marine compounds appearing in the literature. In the same section, a chapter by Blunt and Munro describes the importance of databases in the structural elucidation process while the chapter by Phillips et al. illustrates the elegance of several total syntheses of MNPs, highlighting also the role that these syntheses can play in confirming or revising the chemical structures assigned to marine compounds. Section III illustrates the role of MNPs in chemical ecology, investigating the real purpose driving the production of MNPs and explaining how the coexistence and the interaction of an enormous number of species in the marine environment greatly rely on chemical signaling processes. Section IV is inherently connected to the previous one because it describes the biosynthetic origins of these metabolites, or how they can be acquired from dietary sources and/or symbiotic-associated organisms. A rapidly expanding number of MNP scientists have been investigating the molecular biology and genetics of marine secondary metabolite biosynthesis with the goal of understanding and manipulating their biosynthetic pathways (particularly polyketide and non-ribosomal peptide synthases). If the development of this subdiscipline is able to attain its long-term goal, then the fermentation and cultivation of microbes could offer a practical solution to the problems of short supply of materials, a fundamental and significant issue which has long delayed and stalled the full development of MNP science. Section V illustrates one of the most important applications of the MNP science, namely, the biomedical potential of small molecule natural products. Since Bergman’s discovery of the antiviral and antitumor arabinose-containing nucleosides “spongothymidine” and “spongouridine” from Cryptotethia crypta in 1955, the potential of marine organisms in pharmaceutical applications has been the driving force of many of these scientific investigations. At the moment, five marine-derived drugs have been approved by the FDA or EMA (the EU agency), namely, two nucleosides (cytarabine and vidarabine), a polypeptide (ziconotide), the complex alkaloid trabectedin (ET-743), and the fantastically complicated synthetic derivative, Halaven, of the sponge metabolite halichondrin. Moreover, a further 15 compounds are in different phases of clinical trial and several hundred promising compounds are in preclinical stages. The eight chapters of Section V illustrate different aspects of the biomedical potential of MNPs, highlighting how this “natural library” can contain lead compounds to be used as an inspiration to design and develop new useful therapeutic agents, or to gain initial information about the pharmacophore and structure-activity relationships. ▶ Chapters 20, ▶ 21, and ▶ 23 describe some specific pharmacological activities of small marine organic molecules, while ▶ Chaps. 24 and ▶ 25 are focused on the potential use of marine macromolecules, fluorescent proteins, and biologically formed polymers of silica, respectively. The last two chapters of Section V discuss the long-standing and perplexing problem of compound supply, an inherent feature of working in the marine environment, and the legal and ethical issues connected to the exploitation of this environment. With the growing number of commercial xxiv Introduction applications of MNPs, it is critical for practitioners of this field to possess a deep knowledge of intellectual property protection and constraints on public disclosure. Finally, Sect. VI includes two chapters reporting on marine toxins, one of the oldest fields of MNP chemistry but one still very active and interesting for its toxicolog- ical, pharmacological, and economic implications. We cannot conclude this introductory chapter without thanking the friendly contributions of all of the colleagues that accepted the task of providing their invaluable expert knowledge through the preparation of the different chapters. We hope that this handbook on MNPs will succeed in further stimulating enthusi- asm and interest in this relatively young but extremely dynamic and rapidly evolving discipline.