Organic Products From The Sea: Pharmaceuticals, Nutraceuticals, Food Additives, and Cosmoceuticals

CHAPTER
Organic Products from the Sea:

Pharmaceuticals,
Nutraceuticals, Food
Additives, and
Cosmoceuticals 27
All figures are available on the companion website in color (if applicable).
27.1 INTRODUCTION
Humans have long used the ocean as a source of food and minerals. The inorganic
resources obtained from the sea are primarily salt, sand, and gravel. In coastal regions
where oysters grow, their shells have been used to formulate a type of concrete called
tabby. Diatomaceous earth is used as an insecticide, a filtration medium, and an abrasive.
Although most of the organic materials harvested from the ocean serve as seafood, an
increasing amount is being used for medicinal purposes, as food additives, in cosmetics,
and as pesticides. Since the 1970s, much effort has been directed at searching the ocean
and its organisms for novel biomolecules. This interest was stimulated by the recogni-
tion that marine organisms are likely to have developed unique biosynthetic pathways to
generate compounds that help them survive the environmental conditions found only in
the oceans. Although many unique compounds have been identified, few new products
have yet to be brought to market. Recent advances in biotechnology, such as genomics
and bioinformatics, are now being used to overcome problems associated with the com-
mercial development of new marine products. As a result, several marine biomolecules
are now in clinical trials for use in treating cancer, infections, Alzheimer’s disease,
and asthma. Others are being tested for use as antifouling agents. These advances are
supported by an interdisciplinary approach involving the expertise of marine biolo-
gists, chemical ecologists, synthetic organic chemists, and pharmacologists, along with
experts in genomics, biotechnology, and mariculture.
In this chapter, a description of the marine organic products in current usage is
provided along with a consideration of how the structures of these molecules con-
fer predictable physiological activities. This is followed by a discussion of the strategic
approach used to discover and develop marine organic products along with the rea-
sons why new products are so hard to bring to market. Finally, some examples of
1
2 CHAPTER 27 Organic Products from the Sea
products now in the development pipeline are presented. These products are being
targeted for use as biomedicines, nutraceuticals, cosmoceuticals, antifouling agents,
pesticides, research probes, and biosensors, and in mariculture and environmental appli-
cations.1 The latter include in situ pollutant degradation and removal of toxic heavy
metals.
27.2 WHAT ARE MARINE NATURAL PRODUCTS?

In this chapter we will focus on the class of organic compounds called natural
products or secondary metabolites. These biomolecules do not play a direct role in
the development, growth, or reproduction of organisms. Not all organisms make sec-
ondary metabolites. Of those that do, their natural products tend to be quite species
specific. The secondary metabolites are generally used by organisms to control ecolog-
ical relationships that involve: (1) defense against predation, parasitism, and infection,
(2) competition for space and food, (3) intraspecies communication for the purposes
of mating, hunting, or quorum signaling, and (4) maintenance of mutualistic symbionts.
Some natural products confer UV protection.
Most higher plants and microbes have secondary metabolites whereas most verte-
brates do not. Because of the species specificity of these compounds, chemical diversity
within a phylum is roughly correlated with species diversity. Most of the marine natural
products (MNPs) are contributed by the seaweeds, sponges, and cnidarians, reflecting
their extraordinary species diversity. This high species diversity is part of the reason
why the oceans have long been considered as having great potential for new drug dis-
coveries. The other reason is inherent in the biological role of natural products—these
biomolecules help organisms cope with particular ecological challenges. The biochem-
ical mechanism responsible for the desirable physiological activity usually involves a
highly specific binding of the secondary metabolite with a target receptor molecule.
Fortunately, enough similarity exists among the molecular structures of the target
receptors in marine organisms and humans that many MNPs exhibit very high phys-
iological activity in humans. The kinds of activities most commonly seen are antibiotic,
anti-inflammatory, antiviral, antioxidant, anticoagulant, analgesic, and antitumorogenic,
giving MNPs great potential in treating bacterial and fungal infections, asthma, immune
diseases like HIV/AIDS, pain, and cancer. Other MNPs have light absorption properties,
making them excellent candidates for use as sunscreens, dyes, and coloring. Some act
as surfactants and, thus, might be useful in preventing biofilm formation, biofouling,
1
A marine nutraceutical is defined as “a marine-derived substance that can be used as a dietary supple-
ment or a food ingredient that provides a medicinal or health benefit beyond basic nutrition” [Barrow,
C., and F. Shahidi (2008). Marine Nutraceuticals and Functional Foods. CRC Press, 494 pp.] Cos-
moceuticals are cosmetic products with druglike benefits conferred by ingredients such as vitamins,
phytochemicals, enzymes, antioxidants, and essential oils.
27.3 History of Marine Organic Products 3
and adhesion of microbes to wounds. Others are excellent metal ligands, giving them
potential as water purifying agents.
During the past 30 years, more than 35,000 novel MNPs have been isolated and
structurally identified. Most of these exhibit bioactivity in arenas that suggest their
potential as a new drug. Many have no terrestrial analog and so represent wholly new
classes of potential drugs. At present, most attention is focused on developing new treat-
ments for cancer. Approximately 150 of the MNPs are presently known to be cytotoxic
against tumor cells, with approximately 35 having a known mechanism(s) of action.
Out of these, at least a dozen are now in human clinical trials. As shown in Table 27.1,
these include ecteinascidin (Yondelis), bryostatin-1, squalamine, aplidin, dolastatin-10,
ILX651, and KRN7000 (␣-galactosylceramide). Another very active area of research lies
in developing uses for marine biomass leftover from commercial fisheries and maricul-
ture operations. In 2000, 100 million tonnes of biomass were harvested, with only half
being used. One successful approach to handling seafood “waste” has been development
of products from Chitosan, a processed form of chitin.
27.3 HISTORY OF MARINE ORGANIC PRODUCTS

Extracts from marine organisms have been used for medicinal purposes in China, India,
the Near East, and Europe since ancient times. As late as the 1800s, many were a part of
standard pharmacopoeias. Scientists have since come to appreciate that many of these
remedies contain potent drugs. Substantial efforts are now being directed to the study
of their active agents. For example, various seaweeds have been used to treat dropsy,
menstrual difficulties, gastrointestinal disorders, abscesses, and cancer. We now know
that seaweeds contain a large number of novel, very potent MNPs, many of which are
halogenated compounds. Sponges, which contain high levels of iodine, have been used
to treat tumors, goiter, dysentery, and diarrhea.
Before the invention of synthetic sponges, natural ones were used for absorbent
purposes in medical settings. For example, anesthetics were delivered by impregnating
a sponge with a soporific. Blood flow was stanched with sponges. Contraceptives, such
as lemon juice and quinine, were held in place with sponges.
Hippocrates recorded that juices from various species of mollusks were commonly
used as a laxative. Extracts from the sea hare, Aplysia, have been used as a depilatory.
Essences from gastropod opercula have been used in perfume and incense. Several
marine snails were a source of blue and purple dyes to the Hebrews and Romans during
biblical times. Given this ancient fund of knowledge, marine scientists have begun a new
field of study called marine ecological anthropology, which seeks to uncover traditional
environmental knowledge likely to yield insights into marine organisms with interesting
MNPs.
Most MNPs currently in common use are food additives, insecticides, nutraceuti-
cals, and ingredients of cosmetics. Some examples are provided in Table 27.2. Products
currently used as drugs or in drug research are shown in Table 27.3 and discussed next.
4
Table 27.1 Marine Natural Products Currently in Clinical Trials (Circa 2007).
Phylum Compound Name Type Origin Disease Applications Clinical Phase
IPL 576,092, Steroid Petrosia contignata Inflammation/asthma II
IPL-512,602, and
IPL-550,260
E-7389 Analog of Halichondrin, Halichondria okadai Cancer III
a macrolide
Taltobulin (HTI-286) & Analog of tripeptide Hemiasterella minor Lung cancer I/II
E7974 Hemiasterlin
a
Porifera LBH 589 and Derivative of Psammaplysilla sp. Advanced or metastatic I
CHAPTER 27 Organic Products from the Sea
NVP-LAQ284 psammaplin A, a NSCLC or malignant

brominated aromatic pleural mesothelioma
amino acid
KRN7000 Glycosphingolipid, Agelas mauritianus Pancreatic cancer and II
␣-galactosylceramide solid tumors
ET-389 Axinella sp. Cancer I
Zalypsis (PM00104/50) Jorumycin and Mollusks and sponges Advanced solid tumors I
Renieramycin analogs and lymphoma
Cnideria OAS-100 Phospholipids Pseudopterogorgia Wound healing, I/II
(methopterosin) elisabethae (soft coral) anti-inflammatory
a
Dolastatin 10 and Polypeptides, dolastatin Dolabella auricularia Soft-tissue sarcomas, II
dervatives, soblidotin analogs (sea hare) metastatic melanoma
(TZT-1027) and
Synthadotin/Tasidotin
(ILX651)
b
Khalalide F Cyclic depsipeptide Elysia rufescens Hepatocellular II
carcinoma, NSCLC and
melanoma. Possible
treatment for psoriasis
PM 02734 Khalalide derivative Elysia rufescens I
Mollusca Spisulosine (ES-285) Aminoalcohol Spisula (=Mactromeris) Cancer I
polynyma (Arctic surf
clam)
Zalypsis (PM00104/50) Jorumycin and Mollusks and sponges Advanced solid tumors I
Renieramycin analogs and lymphoma
CGX-1160 Peptide, conotoxin Conus geographus Pain I
derivative
AM-336 Peptide, conotoxin Conus geographus Pain II
derivative
CGX-1007 Peptide, conotoxin Conus geographus Pain and epilepsy I
derivative
Ectoprocta Bryostatin 1 Macrocyclic lactone Bugula neritina Cancer II
(bryozoan)
(Continued)
27.3 History of Marine Organic Products
5
6
Table 27.1 (Continued)

Phylum Compound Name Type Origin Disease Applications Clinical Phase
Nemertea GTS-21, DMXBA Anabaseine analog Amphiporus lactifloreus Alzheimer’s/schizophrenia I/II
Aplidine Depsipeptide (analog of Aplidium albicans Multiple myeloma, I/II
(dehydrodidemnin B) didemnin) (tunicate) leukemia, melanoma,
renal and other solid
tumors
a
Yondelis/Trabectedin Tetrahydroisoquinolone Ecteinascida turbinata Soft-tissue sarcomas, I/II/III & Clini-
(Ecteinascidin 743) alkaloid (tunicate) ovarian, prostate, cal Use
breast, and solid tumors
Chordata Staurosporine, Alkaloid Eudistoma toealensis Cancer, multiple I
N-benzoylated (PKC41) (tunicate) & its myeloma
predatory flatworm,
Pseudoceros sp.
Squalamine lactate Aminosterol Squalus acanthias Ovarian cancer and III
(MSI-1256F) (shark) NSCLC
CHAPTER 27 Organic Products from the Sea
Neovastat (AE-941) Crude extract Squalide (fish) I-II: Prostate Cancer. III
III: Kidney and NSCLC
Tectin, tetrodin Alkaloid Tetradontiformes (fish) Sodium channel blocker II/III
(tetrodotoxin)
Neptune Krill Oil Phospholipids Krill Premenstrual syndrome II
Microbes Salinosporamide A Alkaloid Marine obligate Multiple myeloma I
(NPI-0052) actinomycete
Fungus NPI-2358 Halimide Aspergillus sp. solid tumors and I
(diketopiperazine) lymphomas
a
Possible bacterial source
b
Possible green algal source
NSCLC = non-small cell lung cancer
Table 27.2 Examples of Marine Natural Products in Current Use as either Pharmaceuticals, Food Additives, Insecticides,
Nutraceuticals, and Cosmoceuticals.
Products Specific Product Source Uses Trade Name or
Production Company
Algal polysaccharide Carrageenans, agar, Red algae Cosmetics, thickeners, Marine Colloids (USA),
alginates anticoagulant, antiviral, Danisco (Denmark),
pharmaceuticals SOBALG (France)
Glycosaminoglycans Chondroitin sulfate Fish Cosmetics, tissue replacement, CTTP (France)
anticoagulant
Collagen Cosmetics, artifical tissue
Chitosan ␤-(1-4-N-Acetyl) Crustacean Cosmetics, wound dressings,
glucosamine shells, fungi microencapsulation
Lipids Long-chain Microalgae, Prevention of heart disease, BIONAGROL 3000,
polyunsaturated fatty seaweeds, fish mental development in AGE OMEGA 3
acids (arachidonic acid, premature children, antitumoral, (Arkopharma), MAXEPA
eicosapentaenoic acid, lipid metabolism (Pierre Fabre
and docosohexaenoic Medicament)
acid [DHA])
Hormones, cyclic Fish Antioxidant, immunostimulants, Promarine
peptides hydrolysates nutraceutical products
Peptides Antifreeze glycoproteins Polar fish Cell protection during cold A /F Protein
storage (animal and human
eggs, blood platelets) and
improved quality of frozen foods
Carotenoids Astaxanthin Krill, algae Red-colored food additive for Numerous companies
maricultured salmon and shrimp marketing under various
used to enhance red color; trade names
antioxidant
27.3 History of Marine Organic Products
Source: After Mantoura, F. (ed.) (2001). Marine biotechnology: A European strategy for marine biotechnology. ESF Marine Board Feasibility Study Group
Report, ESF Marine Board Position Paper 4, p. 8.
7
Table 27.3 Marine Natural Products Currently Being Used as Drugs or in Drug Research.
Product Trade Name and Chemical Class Application Original Source Method of Production
Marketer (Year of
Commercialization)
Aequorin Bioluminescent calcium Bioluminescent jellyfish Recombinant protein
indicator Aequora victoria
Ara-A Vidarabine Nucleoside (amino-6- Antiviral drug (herpes Marine sponge Microbial fermentation
beta-D-arabino- infections) Cryptotethya crypta of analog
furanosyl-9, 9h-purine)
Ara-C Cytosar-U, Cytarabine Nucleoside Anticancer drug Marine sponge Chemical synthesis of
(1972) (4-amino-1-beta-D- (leukemia and Cryptotethya crypta analog
arabinofuranosyl- non-Hodgkin’s
2(1H)-pyrimidinone) lymphoma)
Calyculin A AG Scientific Polyketide Molecular probe: Sponge Discodermia Extracted fron the
selective inhibitor of calyx sponge
protein phosphatase 1
Cephalosporins (1965) ␤-Lactam Antibiotic (antibacterial Marine fungus Semisynthetic antibiotic
by inhibition of Cephalosporium derivatives of
mucopeptide synthesis) acremonium cephalosporin C
FormulaidTM Martek Biosciences Fatty acids: DHA, Nutritional supplements Marine microalgae Cell culture
EHA
Green fluorescent Protein Reporter gene Bioluminescent jellyfish Recombinant protein
protein Aequora victoria
Kainic acid (early 1900s) Amino acid Antihelmintic, Red alga Digenea Extracted from Digenea
Insecticide, simplex simplex, found mainly
neuroexcitatory near Japan and Taiwan.
and neurotoxic Chemical synthesis
activity
Limulus amebocyte BioWhittaker, ErtelAlsop Detection of Horseshoe crab Limulus Amebocytes of the
lysate endotoxins polyphemus horseshoe crab
associated with
gram-negative
bacteria
Manoalide BIOMOL Res. Lab., A.G. Nonsteroidal Molecular probe; Marine sponge Luffariella Wild harvest of sponge
Scientific, Inc., Novagen, sesterterpenoid phospholipase A2 variabilis
Inc. inhibitor
Hydroxyapatite Pro Osteon Implant 500, Bone implant
Interpore International
(1992)
Okadaic acid AG Scientific, Polyketide Molecular probe: Sponge Halichondria Cell culture
Sigma-Aldrich selective inhibitor okadai and dinoflagellate (Prorocentrum
of protein Prorocentrum concavum concavum)
phosphatase 1
(Continued)
Product Trade Name and Chemical Application Original Source Method of
Marketer ( Year of Class Production
Commercialization)
Phycoerythrin ProZyme, OSMAN Conjugated antibodies Red algae, Porphyridium Cell culture
International Group S.A. used in ELISAs and flow cruentum and others
cytometry. Fluorescent
protein and/or
antibody-label in
biotechnology as well as
colorants in cosmetic
and food industry
ResilienceTM Estee Lauder ‘Marine extract’ additive in Caribbean gorgonian Wild harvest of
skin creams Pseudopterogorgia gorgonian coral
elisabethae
Salmon calcitonin Rhone-Poulenc Polypeptide Paget’s disease of bone, Salmon Oncorhynchus Chemical synthesis
CalcimarTM Rorer/Aventis (1975) and hypercalcemia and spp.
Novartis as Myacalcin postmenopausal
(1995) osteoporosis
Tetrodotoxin Tocris, Koma Biotech, Alkaloid Molecular probe: selective Order Tetrodontiformes Fishing
etc. inhibitor of Na+ channel
conductance
Vent DNA New England Biolabs Polymerase chain reaction Hydrothermal vent Recombinant protein
polymeraseTM enzyme archaean Thermococcus
litoralis
Ziconotide Prialt, Elan Corporation Peptide Pain management Mollusk Conus magus Chemical synthesis
(2004)
ELISA = enzyme-linked immunosorbent assay
27.4 Chemical Ecology and Structure-Activity Relationships 11
27.4 CHEMICAL ECOLOGY AND STRUCTURE-ACTIVITY

RELATIONSHIPS
Secondary metabolites have evolved under the pressure of natural selection for a cer-
tain purpose and mode of action. Because of the uniqueness of the marine environment,
the necessary adaptations have resulted in novel secondary metabolites that are highly
specific for their target receptors. Terrestrial plants and microbes have also evolved
unique species-specific natural products. Indeed, evolutionary selection can be viewed
as a type of natural drug development process in which structures have become opti-
mized for their biological activity. Thus, it is not surprising that about half of the drugs
in current use were discovered as natural products.
Marine organisms have long been recognized as likely to contain many potential
novel drugs because of the environmental conditions that are unique to their habitat.
These conditions include high ionic strengths, low light levels, cold temperatures, and
high pressures. Halides, such as bromine and iodine, are relatively abundant components
in marine metabolites, reflecting their high concentrations in seawater. Another unique
adaptation seen in many marine organisms is bioluminescence. Intense competition for
space, light, and nutrients, especially in populous benthic areas such as coral reefs, has
favored development of a range of chemical mechanisms for warding off competitors
and rapidly assimilating nutrients and light. Most of the lower invertebrates that do not
have hard outer coverings, such as sea cucumbers and sea squirts, tend to have MNPs
that act as chemical deterrents to predation. Thus, the standard rule of thumb among
MNP chemists is that fat, fleshy, slow-moving, and brightly colored animals are likely to
harbor MNPs. Finally, reproduction in the marine environment presents challenges that
are quite different from those encountered on land. A common adaption is the use of
MNPs as an attractant to locate a mate or induce spawning.
To date, most marketed marine products have come from shallow and often tropical
marine organisms, due mainly to the ease of collecting them. But increasing scientific
interest is now being focused on the potential medical uses of organisms found in the
deep sea. These organisms have developed unique adaptations that enable them to sur-
vive in dark, cold, and highly pressurized environments. Another relatively unexplored
category of organisms are marine microbes, which are likely to contain novel substances
due to their unique metabolic pathways.
MNPs are highly diverse in structure. They include terpenes, halogenated com-
pounds, alkaloids (which contain nitrogen), and polyketides. The last are large multien-
zyme protein complexes that contain a coordinated group of active sites. Their potent
physiological activity and receptor-binding specificity are the result of a well-defined,
complex three-dimensional structure rich in stereochemical centers, concatenated rings,
and reactive functional groups. These functional groups enable hydrogen bonding and
other intermolecular interactions. MNPs that are involved in enzyme systems tend to
have maximal reactivity between 5 to 12◦ C instead of the 30 to 35◦ C characteristic
of their terrestrial counterparts. (Thermophilic microbes living in hydrothermal ecosys-
tems are a likely exception to this.) Because of the complexity of their chemistry, many
of their physiological effects are highly dependent on environmental conditions.
The molecular structures characteristic of MNPs differ from those favored by organic
chemists, whose approach toward synthetic drug development focuses on creating low-
molecular-weight compounds with few stereochemical centers and a relatively low
degree of chemical reactivity. The latter confers stability to the drug molecules. In
many cases, MNPs are too bioactive and have too many negative side effects to be
useful drugs. In these cases, MNP chemists create analogs of the original compound
in which undesirable bioactivity is eliminated, or reduced, through structural modifica-
tions. Thus, MNPs are generally used as a starting pointing for development of a new
drug. To accomplish these “redesigns,” MNP chemists must understand structure-activity
relationships.
27.5 THE DISCOVERY AND DEVELOPMENT OF MARINE

PHARMACEUTICALS
The process of discovering and developing new pharmaceuticals is a long and arduous
process. In 2001, the Tufts Center for the Study of Drug Development estimated that
for the average new drug, this process took 10 to 15 years and $800 million (USA).
Much of this time and cost is associated with safety and efficacy testing required by
the U.S. Food and Drug Administration. For every 5000 potential drugs that make
it to the initial stages of required testing, only five undergo clinical trials, with one
eventually being approved for patient use. Compounds derived from terrestrial natural
products constitute about half of the pharmaceuticals currently in use, with most of
the rest being based on completely synthetic structures. Fewer than a dozen drugs
now in use are derived from MNPs. This is partly because a systematic search for
bioactive MNPs began only in the 1970s, much later than the search on land. The
latter was greatly aided by bioethnology in which ancient medical knowledge provided
important leads on bioactive natural products present in terrestrial plants. In contrast,
locating marine organisms most likely to contain useful MNPs requires underwater sur-
veys and collections. These activities were greatly limited until development of SCUBA
and ROVs.
Because of the costly and risky nature of drug development, few MNPs have made it
to market. This situation is likely to change for two reasons: (1) the rate of discovery of
new terrestrial natural products has slowed and (2) the promise of combinatorial tech-
niques in developing synthetic drugs, as promoted in the 1990s, has not been realized.
Thus, MNPs are increasingly being recognized as an important source of potential new
drugs. In addition, several technological advances have resolved long-standing problems
associated with isolation, structure identification, design of better analogs, and synthetic
production of MNPs. As a result, more than 20 compounds derived from MNPs are now
under clinical trials (Table 27.1).
The most critical areas of research are targeted at finding natural products for
treatment of the disease targets listed in Table 27.4. As discussed in the following
27.5 The Discovery and Development of Marine Pharmaceuticals 13
Table 27.4 Most Critical Disease Targets for New Drug Development.
Disease Type Example
Infectious Antibiotic-resistant pathogens
Neurological Parkinson’s and Alzheimer’s disease
Cardiovascular Arteriosclerosis
Immunological Lupus and eczema
Antiviral HIV
Anti-inflammatory Arthritis
Oncological Cancer
sections, MNPs have been identified that collectively have the potential to treat all but
neurological and cardiovascular diseases, although as regards the latter, antilipemic activ-
ity (cholesterol-lowering) is common. Other biomedical applications include repair of
bones and the prevention of biofilm formation. The latter serves to inhibit microbial
infection.
27.5.1 Marine Bioprospecting

The first step in drug discovery is the identification of marine organisms likely to contain
novel natural products. This process is termed bioprospecting and relies on insights
from the field of marine chemical ecology. The latter seeks to understand how marine
organisms use natural products to: (1) compete for resources, (2) maximize reproductive
success, and (3) prevent predation, parasitism, and disease. These compounds include
toxins and attractants. In many cases, the natural products are created by a symbiotic
microbe or prey. The active compound is then concentrated in the tissues of the host
or predator. MNPs tend to be highly species specific because they represent adaptations
to survival in a particular type of environment.
The first step in bioprospecting is observation of species characteristics and behav-
iors. For example, slow-moving animals with no hard outer coverings are likely to use
toxins to prevent predation. These include soft-bodied sessile invertebrates, such as
tunicates, soft coral, and sponges. Some ancient knowledge of these types of bioac-
tivity can be found in indigenous populations. Efforts to collate this knowledge are
being conducted by marine ecological anthropologists. This has led to two concerns:
(1) that indigenous cultures benefit from their environment’s genetic resources, and
(2) that efforts be made to preserve marine biological diversity. To address this, the
UN Convention of Biological Diversity was signed in 1992. It establishes sovereign
rights over biological resources. It also seeks to create mechanisms for the sustainable
use of these resources and ensures equitable distribution of the resulting benefits. In
the case of developing countries, the Convention requires compensation for access
to genetic resources and the provision of assistance in protecting marine biodiver-

sity. All marine bioprospecting efforts must now comply with the stipulations of this
Convention.
27.5.2 Isolation and Screening

Once an organism is collected, it is screened for potentially useful natural products.
This screening technique has to be fast, as hundreds of organisms can be collected
at a time. Screening typically starts by homogenizing the whole organism or some
selected organ in a blender along with a solvent whose polarity can range from polar
to nonpolar. Since “like dissolves like,” the polarity of the solvent will determine
which MNPs are solubilized from the tissues. The resulting “crude extracts” poten-
tially contain hundreds or even thousands of compounds. By varying the polarity of
the solvent, different MNPs can be solubilized and, hence, a family of crude extracts is
generated.
The crude extracts are subjected to a battery of bioassays designed to detect interest-
ing levels and types of biological activity. Bioassays typically involve exposure to intact
tissues or cells. For example, bioassays designed to identify cancer drugs use cancer
cells from humans or rodents. Increasingly, these bioassays are being designed to assess
activity against a specific molecular target involved in treating diseases, such as inhi-
bition of mitosis (cell division), promotion of apoptosis (cell death), or inhibition of
specific enzyme activity (Table 27.5). This approach provides an understanding of the
biochemical basis by which the natural products act. This knowledge enables devel-
opment of optimal methods for drug delivery and dosage levels. New bioassays have
had to be developed to accommodate the biochemical mechanisms by which marine
natural products act, as they are quite different from those exhibited by drug molecules
of terrestrial and synthetic origin.
Some bioassays, such as those used to detect antibiotic activity, are so fast and
inexpensive that they can be done in the field. Most bioassays require sophisticated
equipment and extended periods of time and, hence, must be done in a laboratory. By
using robotic technology, systems have been developed to enable performance of thou-
sands of bioassays per day. The results are used to identify the crude extracts that have
the highest degrees of interesting bioactivity. Various separation technologies are then
used to fractionate these extracts so as to isolate the bioactive compound(s). Much
effort is currently being directed at developing bioassays that can identify whether a
drug candidate has any potentially harmful biological effects.
Bioassays have demonstrated that more than 10% of marine organisms contain cyto-
toxic substances as compared with 2 to 3% of terrestrial species. These toxins occur
more frequently in marine invertebrates than in marine algae, in sessile rather than
motile species, and in tropical rather than temperate or cold-water animals. Marine tox-
ins do not generally make good drugs because they are usually too powerful. Instead
they are used as model compounds in the study of biochemical mechanisms and for
the synthesis of less toxic analogs.
27.5 The Discovery and Development of Marine Pharmaceuticals 15
Table 27.5 Molecular Targets of Various Bioassays Used in Drug Development.

Disease Molecular Target /Mode of Action MNP Drug Treatment
Proteasome inhibitor NPI-0052
Antimitotic, binds to the minor groove of DNA interfering with Yondelis
cell division and genetic transcription processes and DNA repair
machinery
Inhibitor of cell proliferation, promotes the disassembly of actin Spisulosine
stress fibers
Alters the function of the lysosomal membranes inducing cell Khalilide
death by oncosis
Binds to DNA but does not activate DNA damage checkpoint Zalypsis
Microtubule-stabilizing Discodermolide
Cancer Phospholipase A2 Manoalide
Protein phosphatases Okadaic Acid
Protein kinase Bryostatin I
Inhibits secretion of vascular endothelial growth factor related to Aplidine
angiogenesis. Arrests cell cycle at the G1 and G2 phases
Immunomodulatory KRN 7000
Depolymerizes microtubules and blocks cell growth HTI-286
Inhibits tumor cell proliferation Halichondrin E789
Anti-neoplastic activity through inhibition of microtubule assembly Dolastatin 10
Inhibitor of growth-factor-mediated endothelial cell proliferation Squalamine
and migration and angiogenesis
Pain Ion channels Saxitoxin

Nicotinic acetylcholine receptors Conotoxins
27.5.3 Structural Identification and Synthesis

Once a purified extract has been obtained, the next step is structural identification of
the active compound(s). Typically this requires recollection of a large number of source
organisms to provide an adequate supply of material for study. In many cases, this has
proven difficult as a good taxonomic identification is often not possible with inverte-
brates such as sponges. In other cases, re-collection of the species does not provide
extracts with the same bioactivity as the original set. This is thought to reflect the
importance of bioaccumulation of the active compound from prey or from microbial
symbionts whose growth is controlled by environmental conditions. This variability

illustrates the importance of developing synthetic means for generating the MNP. With-
out a reliable source of the purified compounds, clinical trials are not possible. It also
demonstrates the importance of field-based screening techniques for the identification
of organisms with promising bioactivity.
Using various chromatographic technologies, individual compounds are isolated from
the extracts. Most MNPs tend to be unstable at high temperatures, making them una-
menable to gas chromatography. In these cases, high-pressure liquid chromatography
is used. The structure of the compounds is then determined by nuclear magnetic
resonance spectroscopy, mass spectrometry, and x-ray crystallography. This step is chal-
lenging as most MNPs are large heteroatomic molecules with complex three-dimensional
features.
With the exception of seaweeds, wild collection is not considered a long-term supply
option due to high cost, unreliability, and environmental impacts. More feasible options
include: (1) mariculture of organisms or cell lines, (2) chemical synthesis performed on
an industrial scale, or (3) production from microbes genetically engineered to synthe-
size the compounds. Mariculture is not an easy proposition and, hence, few organisms
are currently being grown commercially for the purposes of drug production. No con-
tinuous cell lines have been established. Both of these approaches are deemed risky as
microbial symbionts could be critical to the formation of the MNP and, hence, would
require cultivation along with their host.
More success has been achieved from chemical synthesis, although this has proven
challenging given the large sizes and complicated structures found in MNPs. In some
cases, as many as 60 steps have been required to effect a complete synthesis from simple
starting products. In most cases, this is not commercially feasible. One solution has been
to identify smaller versions of the MNP that have similar structures and bioactivity,
but are easier to produce. These analogs can also be designed to eliminate or reduce
undesirable biological side effects. Another synthetic approach is to insert genes into
microbes to enable them to synthesize the MNP. These microbes are grown on a large
scale in purified cultures from which the MNP can easily be extracted.
27.5.4 Clinical Trials, Marketing, and Patents

All substances sold as drugs in the United States must be approved by the federal Food
and Drug Administration. This approval process requires a series of phased drug trials
as illustrated in Figure 27.1. The first phases involve animal testing. If no adverse side
effects are observed and significant ameliorative effects are found, testing on human
subjects is undertaken. This process can take years because of the need to check for
long-term effects and to optimize methods for drug administration and dosage.
The last stage in drug development is an assessment of the market potential for the
drug. If a manufacturer is not able to realize a large enough profit, the drug will not
be brought to market. Thus, business experts must assess whether the potential market
niche is large enough to provide an acceptable return on investment. This assessment
must now include the costs of “reimbursing” the country from which the originating
27.6 Examples of Marine Natural Products 17
1
Review and approval by
Food & Drug Administration Compound
approved
Phase III: Confirms effectiveness and monitors
adverse reactions from long-term use in 1,000
to 5,000 patient volunteers.
Phase II: Assesses effectiveness
and looks for side effects in 100 to
500 patient volunteers.
Phase I: Evaluates safety and
5 Compounds enter
dosage in 20 to 100 healthy
human volunteers. clinical trials
5,000 Compounds Discovery and preclinical testing:

Compounds are identified and evaluated in
evaluated laboratory and animal studies for safety,
biological activity, and formulation.
0 2 4 6 8 10 12 14 16
Years
FIGURE 27.1
Clinical drug trials required by the U.S. Food and Drug Administration with estimated time required
for completion. Source: From Brennan, M. B. (2000). Drug discovery: Filtering out failures early in
the game. Chemical and Engineering News, June 5, 2000, pp. 63–73.
marine organism was first collected. In cases where the market return is insufficient,
the United States provides resources under the Orphan Drug Act of 1983 to support
further commercial development of promising drug candidates.
27.6 EXAMPLES OF MARINE NATURAL PRODUCTS

MNPs have been classified by their molecular structure, biosynthetic pathway, and
organismal source. The most common molecular types and their biosynthetic path-
ways are shown in Table 27.6. About half of MNPs are generated via the isoprenoid
pathway, and most of the remainder are evenly split between the amino acid and aceto-
genin pathways. Many important antibiotics and anticancer drugs are polyketides. Their
anabolic formation pathway involves a stepwise polymerization of simple 2-, 3-, and
4-carbon functional groups, such as acetyl-CoA, propionyl CoA, and butyryl-CoA. The
other pathways contribute a minor number of MNPs.
Some examples of MNPs that are in current use or are in clinical trials are presented
in the following sections, sorted, for the most part, by phylum. To date, the majority
of MNPs have been isolated from sponges, although this may simply reflect a relative
lack of work on microbes and fungi. Other major organismal sources of MNPs are the
coelenterates (soft corals and gorgonians), echinoderms, tunicates, mollusks, and bry-
ozoans. Some crustaceans and fish are important sources of nutraceuticals and other
organic products.
Table 27.6 Biosynthetic Pathways of Natural Products and

Representative Examples.
Biosynthetic Pathway Structural Class

Isoprenoid Terpenes
Steroids
Carotenoids
Quinones
Acetogenin Polyketides
Polyphenols
Fatty acids
Prostaglandins
Amino acid Peptides
Alkaloids
Shikimate Cinnamic acid derivatives
Flavonoids
Coumarines
Nucleic acid Nucleic acids
Nucleo bases
Carbohydrate Sugars
Polysaccharides
Source: From Harper, M. K., T. S. Bugni, B. R. Copp, R. D. James, B. S.
Lindsay, A. D. Richardson, P. C. Schnabel, D. Tasdemir, R. M. Van Wagoner,
S. M. Verbitski, C. M. Ireland (2001). Introduction to the Chemical Ecology of
Marine Natural Products, In Marine Chemical Ecology, J. B. McClintock and
B. J. Baker, eds, CRC Press, p. 3–566 (Table 1.1, p. 5).
27.6.1 Macroalgae: Seaweeds

The macroalgae or seaweeds are classified by their pigments into the Chlorophyta
(green algae), the Phaeophyta (brown algae), and the Rhodophyta (red algae). There are
approximately 900 green, 4000 red, and 1500 brown species of seaweed. Red seaweeds
are found mostly in subtropical and tropical waters, while brown seaweeds are more
common in cooler, temperate waters. Around 220 species of seaweed are harvested
commercially, with about half used for food and the rest for phycocolloid production.
Phycocolloids
Phycocolloids are high-molecular-weight polysaccharides isolated from the cell walls
and mucilage of seaweed as noncrystalline materials or gums. They include agar, car-
rageenan, and algin. Agar is obtained from red algae, mostly Gelidium and Gracilaria.
It is a variable mixture of several polymers whose most common repeating units are
agarose (27.1) and agaropectin (27.2). A significant amount of the agarose also contains
acidic residues, primarily sulfate and pyruvate.
Agarose Agaropectin
CH2OH CH2 CH2 CH2OH
HO O HO HO O OH
O HO HO
OH O O
O OH O O
OH OH
Agarose (27.1) and Agaropectin (27.2)
Red algae are also the primary source of carrageenan (27.3), mostly from Kappa-
phycus and Betaphycus.
Partial structure of Carrageenan

CH2OH CH2OSO2
3
R9O O O R9 is usually H
O
OH O but can be SO2 3.
R 5 H or SO2 3.
O OR OSO23
n
Carrageenan (27.3)
Algins are obtained from the cell walls of the brown seaweed species of Laminaria,
known as kelp. Large quantities are harvested off the coast of California by mowing
the fronds. Alginic acid (27.4) is a polymer of two sugar-like units, mannuronic and
guluronic acid.
Partial structure of Alginic acid

COOH
O O
O COOH O
O OH OH O OH OH
Mannuronic acid L-Guluronic acid
Alginic Acid (27.4)
The phycocolloids are water soluble and have excellent gelling, stabilizing, and
emulsifying abilities. Hence, they are widely used in food and cosmetic preparations
(Table 27.7). Agar is used as a culture medium for bacteria because it is not readily
decomposed by microbes. According to the Food and Agriculture Organization of the
United Nations, global production was nearly 10.1 million tons (wet weight) in 2000,
with the majority coming from the brown (71%) and red (20%) algae. Most of this
production occurs in China. Because of their high iodine content, various seaweeds are
also been used to control and cure goiter. Brown seaweeds are notable as a source of
potassium-rich fertilizers and soda ash (Na2 CO3 ), which is an important component of
hard soap.
Table 27.7 Current Uses of Marine Algal Phycocolloids.
Phycocolloid Food Additive Industrial Pharmaceutical Personal Care Other
Products
Agar Canned foods Laxative Ointments and Microbial growth
cosmetics medium
Outer cover of capsules
Carageenan Dairy products: Fertilizers and Anticoagulant, prevents ulcers Lipsticks, soaps, Film, paint,
cottage cheese, ice phytoremediation. In the and cholesterol absorption, toothpaste, shampoos, varnish, buttons
cream, coffee textile industry, it is prevents metal adsorption, lotions, creams
creamers, whipped used as stiffening and antiviral, prolongs the activities
creams, cheese, binding material for a of common analgesics and
yogurt, chocolate soft finish anticough medicines such as
drinks, dips, codeine and ethylmorphine,
puddings promotes the rapid
disintegration of drug tablets
Other: pie fillings,
jams and syrup,
baby food, sauces,
salad dressings,
canned meats,
shrimp and fish gels
Algin Dairy products, beer, Paper coatings and Formulations of drug tablets, Dental adhesive
salad dressings, sizing, textile printing, dental impressions, antacids,
cake mixes, and and welding-rod bandages, and detoxifying
meringues coatings agent
Macroalgal Natural Products

The natural products discovered in red seaweeds include a large number of unique
polyketides and mono-, sesqui-, and diterpenoids that are notable for a high degree of
substitution by chlorine and bromine atoms. An example of the latter are the halo-
genated furanones (27.5) produced by the rhodophyte Delisea pulchra, which appear
to prevent bacteria from colonizing the seaweed’s surface. The ability to prevent biofilm
formation leads to applications in which antibiofouling activity is needed, such as on
marine structures, contact lenses, medical devices, and bandages. These compounds
appear to disarm bacteria, rather than killing them, by blocking their production of
quorum-sensing compounds, the microbial equivalent of intraspecies chemical commu-
nicants. Microbial control via chemicals that prevent biofilm formation is thought to be
less likely to induce resistance following repeated usage.
Furanone
Br Br
Furanone (27.5)
L-␣-Kainic acid (27.6) is another natural product from red algae (Digenea simplex).
It has been used in Japan as an antihelmintic (dewormer). Because it is a neurotoxin,
kainic acid has also been used to induce brain degeneration in test animals thereby
supporting research into Alzheimer’s disease and epilepsy. Kainic acid is produced
commercially from algae specially grown for this purpose.
L-a- Kainic acid

H2C
C CH2COOH
H3C
N COOH
H
Kainic Acid (27.6)
Although not technically a natural product, inorganic extracts from the red algae
Corallina sp. have been developed to serve as bone-replacement materials. These
extracts contain porous fluorohydroxyapatite that is applied onto existing bone to
serve as a graft. One product currently being marketed for dental applications is FRIOS
AlgiporeTM .
Some of the more notable natural products discovered in the brown seaweeds are
the fucoidans and glucans. Interest in their bioactivity stems from the observation that
in Japan, where brown seaweeds are a popular food, the incidence of breast can-
cer is about one sixth the rate of that reported for American women. Laminaria
species commonly consumed in Japan include wakame and kombu. Laminaria and
Sargassum species are used in China as components of traditional herbal medicines for
the treatment of cancer.
The fucoidans are sulfated polysaccharides whose base unit is L-fucose (27.7). Fucose
is a six-carbon sugar whose structure differs from those in Figure 22.9 in having one
fewer hydroxyl group. The most abundant disaccharide repeating units in fucoidans
isolated from variety of brown algae are shown in (27.8).
L - fucose
OH
HO OH
HO O CH3
Fucose (27.7)
Fucoidan preparations have anticoagulant activities making them a suitable sub-

stitute for heparin, which is prepared from mammalian mucosa. The algal source is
preferred because the mammalian source can contain infectious agents, such as viruses
or prions. Like heparin, the fucoids affect many other biological activities, such as
inflammation, cell proliferation and adhesion, viral infection, and fertilization. For exam-
ple, fucoidans from wakame (Undaria pinnatifida) exhibit a strong antiviral effect.
Commercial preparations from this seaweed are available for treatment of the herpes
simplex virus. In vitro clinical tests have demonstrated efficacy as an immune system
stimulant with potential for treatment of breast cancer and HIV/AIDS. Another inter-
esting class of polysaccharides in brown algae are the laminarins. They are sulfonated
glucans composed of (1−3)-ß-D-linked glucose and (1−6)-ß-D-linked glucose with man-
nitol end groups. The laminarins also exhibit strong heparin-like activity and, thus,
could prove useful as anticoagulant, antilipemic, antiviral, or anti-inflammatory agents.
27.6.2 Animals
Porifera
Sponges are the most prolific marine invertebrate sources of MNPs. More than 9000
species have been described, with many as yet unclassified. The great resistance of
sponges to bacterial decomposition suggests they contain potent antibiotic compounds.
Indeed, extracts from more than 100 species have generated antibiotic responses against
a wide spectrum of gram-positive and gram-negative bacteria. The compounds responsi-
ble are primarily brominated cyclohexadienes and polyhydroxybrominated phenols. An
example is the brominated alkaloid, oroidin (27.9).
a. Ascophyllum nodosum/Fucus vesiculosus/Fucus evanescens b. Ecklonia kurome
H
H
O O
H O O
CH3 H CH
3
H 2O3SO H OH
H
HO 2O SO H
H 3
H
O H O
O H
H O
CH3 H
CH3
H 2O3SO H OH
H H
2O SO
3
OSO32 H H
H
O
c. Chorda filum H O
CH3
H R1O H
R2O
H
O H
O
H
CH3
H R3O H
R2O
H
O H
H O
CH3 R15 SO32 or H or COCH3
1
R2O H R O H R2 5 SO32 or H
H R3 5
O H
O H
H CH
3 O
H R1O H H
CH3
R2O
H H R2O H
O H R2O
H O
CH3 OH H
H R1O H
R2O
Fucoidans (27.8)
Oroidin
Br
Br N C O N H C H2C H CH N
H
N NH2
H
Oroidin (27.9)
As much as 50% of a sponge’s biomass can be composed of bacteria, cyanobacteria,

and fungi. The ecological role of these microorganisms is not completely understood,
but in some cases appears to include production of natural products that serve as chem-
ical defense agents for the host sponge. This presents the possibility that commercial
production of their MNPs could be achieved via microbial culturing.
Other alkaloids discovered in sponges have given rise to antiviral and anticancer
drugs, namely, Ara-A (Vidarabine) and Ara-C (Cibarine). These are widely considered to
represent the first generation of marine drugs. They are derivatives of the nucleosides,
spongouridine (27.10) and spongothymidine (27.11), that were first isolated in 1950
from a Caribbean sponge.
Spongouridine Spongothymidine
O O
HOH2C O R
HO HN HN CH3
R R
OH O N O N
Spongouridine (27.10) and Spongothymidine (27.11)
The base sugar unit in these nucleosides is arabinose, in contrast to DNA and RNA,
whose base sugar unit is ribose. Ara-A is currently used in ophthalmic ointments as an
antiviral agent. Other analogs of these alkaloid include AZT, the first drug licensed for
treatment of HIV, and acyclovir, used for treating herpes. Ara-C has been approved since
1969 for treatment of leukemia.
As shown in Table 27.1, several compounds from sponges are now in clinical tri-
als for cancer treatment and control of asthma. Halicondrin B (27.13), a complex
polyketide discovered in the Japanese sponge Halichondria okadai, exhibits tubulin-
stabilizing effects. One analog, E789, is currently in Phase I trials for treatment of cancer.
Some compounds are too toxic for use as a drug, but have instead found a role as a
research tool for study of disease processes. An example is manoalide (27.12), which
was discovered in an Indo-Pacific sponge, Laffariella variabilis. It is a nonsteroidal
sesterterpenoid with anti-inflammatory properties. It works by inhibiting phospholipase
A2 (PLA2 ). This enzyme plays a key role in causing the pain and swelling associated with
inflammatory conditions such as arthritis, psoriasis, and poison oak.
Cnideria
The Cnideria include more than 10,000 described species from which over 1500 MNPs
have been isolated. Most are terpenoids found in the octocorallia, coral, gorgonians, and
zoanthids. As with the sponges, many of these may be synthesized by microbial sym-
bionts. An extract from the Caribbean soft coral, Pseudopterogorgia elisabethae (sea
whip), is currently marketed in a skin cream (Resilience by Estee Lauder). The active
ingredient, pseudopterosin (27.14), is an anti-inflammatory. One analog, methopterosin,
is in Phase I and II clinical trials as a topical anti-inflammatory agent.
Manoalide
CH3 O
CH3 CH3 OH
O
O
CH3 OH
Halichondin
CH3
H H H
O O CH3
H
H O OH OH
O O H
O O O O
H H H
CH2 O
O O H O OH
O O H
CH3 CH3
O
CH2
Manoalide (27.12) and Halichondrin B (27.13)
Pseudopterosin
CH3
H
CH3 O O
HO OH
HO
OH
CH3 CH3
CH3
Pseudopterosin (27.14)
Prostaglandin hormones were first discovered in the 1960s. These simple

lipids were immediately recognized as playing important roles in a great variety
of biological systems, suggesting their potential as a drug for treatment of a wide
variety of diseases. The natural production of prostaglandins by land animals is
too limited to provide sufficient quantities for medicinal use. When the Caribbean
gorgonian coral, Plexaura homomalla, was discovered in 1969 to be producing
extraordinarily high concentrations of prostaglandins (27.15), comprising as much as
1.5% of their dry weight, harvesting was considered as an option to meet medical
needs. Because their prostaglandins lack significant biological activity, they would
have had to be chemically modified into mammalian forms (27.16). Fortunately,
synthetic techniques have been developed for production of commercial quantities
of mammalian prostaglandins.
Two photoproteins, aequorin (27.17) and green fluorescent protein (GFP), have
been isolated from luminescent jellyfish (notably Aequorea victoria) and are now in
Gorgonian Mammalian Prostaglandins

O O
COOR2 COOR2
CH3 CH3
R1O H H OR1
(15 R)2PGA2 (15 S)2PGA2
R1 5 H or CH3CO–– R1 5 H or HCO ––
R2 5 H or CH3 R2 5 H or CH3
Gorgonian (27.15) and Mammalian Prostaglandins (27.16)
Aequorin
Aequorin (27.17)
Source: From Head, J. F., S. Inouye, K. Teranishi, and O. Shimomura (2000). The crystal
structure of the photoprotein aequorin at 2.3 Å resolution. Nature 405, 372–376.
commercial use. Aequorin is used as a very sensitive bioassay for intracellular calcium
because the organometallic complex is fluorescent. This has proven useful in diagnosing
cardiac irregularities and metastatic carcinoma because both cause subtle changes in
serum calcium levels. Aequorin was initially obtained via extraction from jellyfish but is
now produced from microbial cultures using recombinant techniques. GFP is used as a
research tool in the field of recombinant genetics. Because of its green fluorescence, GFP
serves as a highly sensitive molecular marker of gene expression.
Echinodermata
Although 7000 species of echinoderms have been classified, a relatively small num-
ber of MNPs have been isolated from this phylum, probably because these animals
have other means by which to deter predators. Some burrow, some have calcified sur-
faces, and many are quite mobile. Some examples of MNPs from this phylum include
dihydromarthasterone (27.18) from starfish, and holothurin (27.19) from sea cucumbers.
Holothurin
Dihydromarthasterone
O O
O
O OH
S4 S3 S2 S1 O
OSO3Na
HO H
H
OH Variable fatty acid composition is indicated by S1 – S4.
Dihydromarthasterone (27.18) and Holothurin (27.19)
A number of steroids isolated from starfish, such as dihydromarthasterone, are toxic

to fish and mollusks. They also have anti-inflammatory, antitumoral, and hemolytic activ-
ity. Some are used by the Japanese to kill fly larvae. This toxic effect is attributed to
their surfactant nature, which causes a disruption in the molting process. Holothurin is
a steroidal saponin that contains sulfate. This compound has been observed to suppress
tumor growth and slow amoeboid movement. It also increases leukocyte phagocytosis
(the destruction of foreign particles such as bacteria) by white blood cells. Holothurin
also exhibits antifungal and cardiotonic activity.
Mollusca
The phylum Mollusca contains 50,000 species that have yielded a number of interesting
MNPs. Murex brandaris and two other species of gastropod snail were a source of the
blue dye, indigo, and Tyrian purple (27.20) to the Hebrews and Romans during biblical
times. These dyes were highly prized for their deep hues and color-fast nature. As a
result, they were restricted to religious and government use. Only the Roman emperor
was permitted to wear “true” purple as produced by Tyrian purple.
The snails emit precursors of these azo dyes as a clear fluid that also contains several
toxic compounds, some of which probably repel predators. Upon exposure to O2 and
sunlight, enzymatic actions convert the precursors to a white, yellow, green, and finally
blue or purple color. Variations in the color of the final products are related to differ-
ences in sex, species, and in situ environmental conditions, as well as the method of dye
processing. Knowledge of the latter was lost by 760 AD and subsequently rediscovered
in 1856. The purple gland of the Murex is also a source of urocanylcholine (27.21),
Tyrian purple
H O H H
H C C N C Br
C C C C
C C
C C C C
Br C N C C H
H H O H
Tyrian purple (27.20)

TM
which is sold under the trade name Murexine as an insecticide. This compound is a
strong paralytic. At low concentrations, it is used as a muscle relaxant, having nicotinic
and curariform actions.
Urocanylcholine
1
N CH CH CO2CH2CH2N(CH3)3
N
H
Urocanylcholine (27.21)
An analog of one molluscan natural product was recently approved for use as a
pain killer. Ziconotide (27.22), marketed as PrialtTM , is an analog of a conotoxin. These
Ziconotide
H2N Cys1 Lys2 Gly3 Lys4
H 2N Cys25 Ala6 Gly5
Cys16 Cys15 Asp14 Tyr13
Lys24 Thr17 Lys7 Met12
Gly23 Gly18 Cys8 Ser9 Arg10 Leu11
Ser22 Ser19
Arg21 Cys20
Ziconotide (27.22)
compounds are peptides composed of 10 to 30 amino acids synthesized by the cone

snail, Conus magus. They are used to immobilize prey (worms and fish). Ziconotide
appears to suppress pain by targeting and blocking specific ion channels in neurons.
This short circuits neurotransmitter release in the nerves that transmit pain signals.
While very effectively blocking pain, Ziconotide still allows the rest of the nervous
system to function properly, unlike other opiates.
Several molluscan natural products are now in clinical trials. They include the dolas-
tatins, kahalalide, and ES-285. The dolastatins are polypeptides isolated from the marine
mollusk Dolabella auricularia (a sea hare) found in the Indian Ocean. They are pos-
sibly of cyanobacterial origin. Two analogs, dolastatin 10 (27.23) and dolastatin 15, are
currently in Phase I and II clinical trials for cancer. Kahalalide (27.24), a depsipeptide iso-
lated from Elysia ruferensces, is in Phase II cancer trials. This bioactive compound might
be synthesized by algae or Vibrio species. Spisulosine (27.25), from Spisula polynyma,
is also presently in cancer trials.
Dolastatin
O
N OMe
N
O NH OMe O O
N
N(Me)2 HN
S
Me5methyl
Dolastatin (27.23)
MNP chemists are also investigating the potential use of the active compounds in
byssal threads for medical applications such as gluing bones and teeth. Marine mussels
use byssal threads for anchoring to surfaces. The threads are extraordinarily strong.
Structurally, they are composed of heavily crosslinked copolymers of collagen and the
protein elastin.
Ectoprocta
This phylum includes the bryozoans. One species, Bugula neritina, is a source of bryo-
statins, a family of 16 acetogenins. Bryostatin I (27.26) is in Phase II trials for treatment
of cancer. A sustainable supply is currently being produced via mariculture. This is chal-
lenging because 14 tons of bryozoans are required to generate an ounce of bryostatin.
The acetogenic polyketide structure of bryostatin I suggests that it is probably gener-
ated by a symbiotic microbe. If this is the case, genetic engineering could potentially
be used to insert the active gene into easily culturable bacteria, providing a means by
which large quantities of bryostatin could be produced.
Kahalalide
CH3
H2N O CH3
O
O N
NH H NH
O O CH
CH3 CH3
N O
CH3 CH3 CH3 HN CH3
O HN O
O NH
O
CH3 NH
CH3
O NH H
HN N
CH3 CH3
O CH3
H O O
N
HO
CH3
CH3 NH
CH3
O CH3
CH3
Kahalalide (27.24)
Spisulosine
OH
1
NH3 2CI2
Spisulosine (27.25)
Bryostatin I
O
O
O
H O
O OH
H H
HO O
H
H H
O OH O
O O H O
OH
H
O H
O
Bryostatin I (27.26)
Annelida
Dead annelid worms have long been used to repel and kill flies. The substance
responsible for this insecticidal activity is nereistoxin (27.27), a disulfide isolated from
the marine worm, Lumbriconereis heteropoda. A synthetic derivative, padan (27.28),
has been marketed under the trade name CartapTM since 1967 as a substitute for
dichlorodiphenyltrichloroethane (DDT) and hexachlorocyclohexane (BHC). The insec-
ticide works by blocking the ganglionic action of the central nervous system. This is
quite unlike the mode of action for the halogenated pesticides, such as DDT. As a result,
padan is nontoxic to mammals and decomposes readily, making it an important addi-
tion to the antibug arsenal. It is used extensively in Asia and Japan against rice stem
borers.
Nereistoxin Padan
CH3 CH2 S CH3 CH2 S CONH2
N CH N CH
CH3 CH3
CH2 S CH2 S CONH2
Nereistoxin (27.27) and Padan (27.28)
Nemertea
Nemertines are a phylum of carnivorous marine worms that possess a variety of alka-
loidal, peptidic, and proteinaceous toxins. These MNPs serve as chemical defenses
against potential predators. Anabaseine (27.29) was the first of these alkaloids to be
identified and has insecticidal properties. It also stimulates a wide variety of animal
nicotinic acetylcholine receptors. An analog, GTS-21 (27.30), is currently in clinical
trials for treatment of Alzheimer’s disease and schizophrenia.
Arthropoda
The most important commercial product from this phylum is limulus amebocyte lysate
(LAL), which is extracted from the blood of horseshoe crabs, Limulus polyphemus.
The most important use of LAL is in a very sensitive bioassay for endotoxins. These
toxins are fragments of bacterial cell walls and are the cause of most fevers in humans.
Because endotoxins are difficult to degrade, they cannot be destroyed by simple ster-
ilization and, hence, must be removed via filtration. LAL is used to verify drug purity
and cleanliness of medical products, such as vaccines and intravenous fluids. During the
bioassay, endotoxins rapidly react with LAL causing the limulus blood extract to clot.
This bioassay has been in use since the 1970s.
LAL is also used to diagnose bacterial infections, including those of the urinary
track, gonorrhea, endotoxemia, and spinal meningitis. LAL reacts with (1,3)-␤-D-glucan
in blood sera, making it useful as a diagnostic for invasive fungal infections. Potential
applications include detection of bacterial contamination in meat, frozen foods, fish,
and dairy products.
GTS-21
OCH3
OCH3
Anabaseine
N N
N N
Anabaseine (27.29) and GTS-21 (27.30)
LAL is obtained by bleeding wild horseshoe crabs, which are then released with
no ill effect. About 300,000 crabs are caught, bled, and released each year, generating
LAL worth $50 million. Research is underway to develop recombinant techniques for
generating LAL derivatives from microbes so that bleeding of wild horseshoe crabs will
no longer be required.
Chordata
Ascidians
The ascidians are the largest and most diverse of the four classes of tunicates and
the only one with reported MNPs. Hundreds of novel MNPs have been found in the
ascidians. Most are thought to be agents of chemical defense. They are considered to
have potential as antifouling, UV protectant and antioxidant agents. The ecteinascidins
are a family of alkaloid compounds produced by sea squirts, Ecteinascidia turbinata.
Ecteinascidin 743, also known as trabectedin and Yondelis (27.31), is in Phase II and
III clinical trials for treatment of melanoma. Aplidine (27.32), an analog of a depsipep-
tide didemnin isolated from the tunicate Aplidum albicans, is also in Phase II cancer
trials. Staurosporine (27.33), an alkaloid discovered in the marine tunicate Eudistoma
toealensis, inhibits protein kinases and, hence, has potent antitumor activity. An analog,
PKC41, is currently in Phase I trials for treatment of multiple myeloma.
Crustaceans
Many insects, crayfish, and other crustaceans synthesize hormones that induce molting.
These ecdysones are oxygenated cholestanes, a type of sterol. They have potential
applications in mariculture as growth regulators and in the control of insect life cycles.
Crustecdysone (27.34) is one example of a crustacean ecdysone.
Aplidine
Ecteinascidin 743
O
O O
O N
HO O N O
O H O
H H NH H
N OH
N O
S O O
N H
O H O
O OH O N
O O
O
O O N
N
NH
O H O
HO
Staurosporine
H
N O
N N
O
H
H3CO
NHCH3
Ecteinascidin 743 (27.31), Aplidine (27.32), and Staurosporine (27.33)
Crustecdysone
OH
OH
OH
HO
OH
HO
H
O
Crustecdysone (27.34)
The major commercial products from crustaceans are derivatives of chitin, which is a
ubiquitous natural polymer composed of amino sugars (Figure 22.11). Because it forms
most of the exoskeletons of crustaceans, chitin is an abundant component of shellfish
wastes produced by the seafood industry, amounting to approximately 1 million tons
Table 27.8 Uses of Chitosan.

General Specific Application Details
Application
Membranes Blood dialysis
Medical product Bandages for wounds Hypoallergenic, antibacterial,
and burns antifungal, blood clotting
Agriculture Plant growth enhancer Boosts the ability of plants to
defend against fungal
infections
Removal of phosphorus, Flocculation and scavenging
metals, oils and PAHs
Water treatment Filtration process Causes the fine sediment par-
ticles to bind together and
is subsequently removed with
the sediment during sand
filtration
Clarification of wine, Used in combination with Removes yeast cells, fruit par-
mead, and beer bentonite, gelatin, silica ticles, and other detritus that
gel, isinglass, and other causes haze
fining agents
Fiber In paper; packaging, and Yarn, edible food wrap, water-
clothing resistant paper; improves
strength of recycled paper
Nutraceutical Dietary fiber Weight loss, antilipemic
per year. It is a nontoxic, renewable, and biodegradable resource. Controlled deacetylation

of chitin produces a water-soluble material called chitosan. Some of the applications of this
product are listed in Table 27.8. Many are medical in nature, reflecting chitosan’s ability to
efficiently complex metals and natural biomolecules. Another derivative of chitin, called
KylanTM , is used to impart shrink resistance to wool. Chitin is also a source of glucosamine
used as a precursor in drug synthesis and as a nutraceutical. Because it is a selective binding
agent, chitin is also used for isolating enzymes.
Fish
Toxins
Potent toxins are found in several marine fish and shellfish. Most appear to be synthe-
sized by algae and are concentrated in the animals as a result of bioaccumulation (i.e.,
the selective retention of ingested compounds). Because of the large-scale consumption
of fish and shellfish by humans, the resulting toxic effects are a matter of great concern.
Such effects include muscle and respiratory paralysis severe enough to cause death. The
majority of the ill effects are experienced from ingestion of coral reef fish leading to
ciguatera, a “disease” recorded as early as the 1400s by Europeans in the West Indies.
The causative agents, ciguatoxin (27.35) and maitotoxin (27.36), are synthesized by
dinoflagellates. These are some of the most lethal natural substances known. In mice,
the lethal dose of ciguatoxin is 0.45 ␮g/kg and 0.15 ␮g/kg for maitotoxin. Oral intake
of as little as 0.1 ␮g of ciguatoxin can cause illness in a human adult.
Ciguatoxin
HO H H
O O H
H OH
H
O H H H H O H
O O H H
O H H O O
O O
HO H H
H H O O
OH OH H H H H
OH
Me 5 methyl
Maitotoxin
H OH
H
O H
O O O
O
O H H H
OH H H H O O
H H H H H
O O O
O H O
OH H OH
O O H O
H O
O HO H H
NaO HO
S OH OH
HO H H O H H H H O
O OH O O
OH H O O OH H H
HO OH
H H O OH
O OH
O O O O O O
O H H H H H H H
OH O OH H H H H
OH
H
OH OH OH
S O HO HO
OH O
H H
OH ONa OH OH OH
Ciguatoxin (27.35) and Maitotoxin (27.36)
Puffers, ocean sunfish, and porcupine fish all contain tetrodotoxin, which is the
most toxic low-molecular-weight poison known. Biosynthesis of this toxin appears to
be controlled by symbiotic bacteria of the Vibrio species. In pufferfish, the toxin can be
found in their gonads, liver, intestines, and skin. The wild-caught species must be care-
fully prepared for consumption as no antidote is known. Farm-raised pufferfish do not
have tetrodotoxin because they do not harbor the bacteria that produce it. Tetrodotoxin
(27.37) is commercially available in Japan and the United States. It is used as a molec-
ular tool for studying sodium channel conductance. Clinical trials have been proposed
to test its use as a pain killer.
Despite their high molecular weights and complex structures, methods for the total
synthesis of each of these toxins, ciguatoxin, maitotoxin, and tetrodotoxin, have been
Tetrodotoxin
H O2
H2N1
H
H H
N OH O
N O
H HO
H H CH2OH
OH
Tetrodotoxin (27.37)
developed. This is considered a useful step in creating less toxic analogs with potentially
more useful physiological effects.
Other Natural Products from Fish

Several omega-3 polyunsaturated fatty acids (PUFA) isolated from marine fish oils have
been observed to lower blood lipids, such as cholesterol, and have anti-thrombotic and
anti-inflammatory activity. The most common long-chain PUFAs are eicosapentaenoic
acid (EPA) and docosahexaenoic acid (DHA), both of which are currently marketed
as nutraceuticals. Their structures are shown in Table 22.5. Cold-water fish, such as
mackerel, salmon, herring, sardines, black cod, anchovies, and albacore tuna, are rich
sources of DHA and EPA. Some preliminary studies suggest DHA deficiency is a causative
factor in Alzheimer’s disease, schizophrenia, depression, and attention deficit disorder
(ADD). This is thought to reflect the important role that DHA plays in brain and nerve
development as it helps build membranes around nerve cells. Fish oil is also rich in
vitamins A (Figure 22.18d) and D, which promote the healing of wounds, burns, and
abscesses. Cod and halibut liver oil are also used as laxatives.
A small arginine-rich protein, protamine, has been isolated from some marine fish.
Protamine is an antithromboplastic and antiprothrombic agent. It is used as an antidote
for heparin overdosage. By binding with the anticoagulant, protamine inactivates this
drug. Protamine is also used in the preparation of protamine zinc insulin, which is a
long-acting antidiabetic drug. Most protamine used in this application is isolated from
trout and salmon.
Sharks are a source of immunoglobulins, which inhibit cancer lymphocyte activity.
Shark liver oil is used as a bactericide and as an intermediate in the manufacture of
pharmaceuticals. It contains the terpene, squalene (Figure 22.18c), which is used as a
skin lubricant, an ingredient in suppositories, and a carrier of oily drugs. Squalamine,
an aminosterol from the dogfish shark, Squalus acanthias, is an inhibitor of tumor
cell growth. It is in Phase II clinical trials for treatment of ovarian and lung can-
cer. A standardized liquid extract from shark cartilage called Neovastat is in Phase II
trials for kidney, prostate, and lung cancer. This MNP exhibits antiangiogenic activ-
ity. Shark cartilage is also a source of chondroitin sulfate used in the treatment of
osteoarthritis.
Some fish species indigenous to the Arctic and Antarctic oceans contain proteins
and glycoproteins that act as an antifreeze by inhibiting the growth of ice crystals at
subzero temperatures. These compounds are large, having molecular weights ranging
from 3000 to 24,000 daltons. They typically contain the amino acids alanine, threonine,
cysteine, and glutamine. Some are being marketed by A/F Protein, Inc. in the United
States for cryoprotection applications, including cold storage of animal and human eggs
and blood platelets, as well as improved storage of frozen foods.
27.6.3 Microbes
Marine microbes are widely considered to be the most likely source of new natural
products that have potential as drugs. This is based on the fact that they represent the
main pool of genetic diversity. As yet, only a small fraction have been cultured. Hence,
their biochemistry is still largely unknown. The microbial biota with the greatest poten-
tial for new MNPs are the phytoplankton, cyanobacteria, myxobacteria, and fungi. In
many cases, microbes are the true source of MNPs found in animals. Bacterial symbionts
can serve as sources of the MNP or as precursor molecules that are modified by the
host. Other MNPs are synthesized by free-living microbes, with the bioactive substances
being bioaccumulated within food webs.
Another favorable characteristic of microbial natural products is the high likelihood
that they can be easily produced through culturing of genetically engineered bacteria.
Challenges to this approach include a limited knowledge of the optimal growth require-
ments for many marine microbes. In addition, the interesting bioactivities exhibited by
microbial MNPs are, in some cases, the result of community-level interactions. Thus,
MNP chemists are working to develop tools that enable characterization of community
assemblages.
Phytoplankton
As noted earlier, most fish toxins are truly synthesized by dinoflagellates. One of the
toxins responsible for ciguatera, maitotoxin, is produced by Gambierdiscus toxicus.
It is the largest natural nonbiopolymer organic molecule known, having 142 carbon
atoms. Most red-tide organisms produce potent toxins, including saxitoxin, brevetoxin,
and okadaic acid. Diatoms in the genus Pseudo-nitzschia produce domoic acid, which
causes amnesic shellfish poisoning. Okadaic acid (27.38) is synthesized by Prorocen-
trum and Dinophysis and causes diarrheic shellfish poisoning. It is currently marketed
as a molecular probe for the study of phosphatases. Dinoflagellate symbionts may be
responsible for the production of the pseudopterins present in the coral, Pseudoptero-
gorgia elisabethae. An interesting line of research is directed at developing symbiotic
communities of green algae and bacteria that produce H2 for use as an energy source.
Bacteria
Active research is directed at discovering novel products from marine actinomycete bacte-
ria. They are among the most common microbes on the planet and are the source of almost
O OH
H H
O O O
HO
O O
OH H H O
O
H H H
OH
Okadaic acid (27.38)
70% of the world’s naturally occurring antibiotics, all of which come from soil-dwelling
strains. Marine actinomycetes were first discovered in 1969 and are now recognized to be
widespread throughout the oceans. These include a marine-obligate genus, Salinospora,
from which more than 2500 strains have been identified. More than 60 natural products
have been isolated from the marine actinomycetes. For example, salinosporamide A is a
potent inhibitor of cancer growth, including human colon, lung, and breast cancers. In
2005, the first compound isolated from a marine-obligate actinomycete, Salinosporamide A
(27.39), entered preclinical trials. It is a highly potent proteasome inhibitor with potential
for use in the treatment of multiple myelomas.
OH
H O
N
O
O
CI
Salinosporamide A (27.39)
Cyanobacteria synthesize toxins such as microcystin and BMAA, ␤-N-methyl-

amino-L-alanine. Given the broad geographic range of cyanobacteria, widespread
exposure to humans is likely. Concern is directed at understanding these expo-
sures as eutrophication seems to be causing cyanobacterial numbers to increase
(Chapter 28.6.4). BMAA has been implicated in the development of amyotrophic lateral
sclerosis(ALS)/Parkinsonism dementia complex in people living in Guam. Cyanobacteria
are also the likely originating source of the dolastatins (27.23), which are in Phase II
trials for cancer treatment.
Another area of research interest is in enzymes and polysaccharides used by
extremophile bacteria, especially thermophiles. Microbial exopolysaccharides produced
by some mesophilic Vibrio and Alteromonas strains isolated from deep-sea hydrother-
mal vents are currently under evaluation for use in tissue regeneration and treatment
of cardiovascular diseases due to their anticoagulant, antithrombotic, and proangiogenic
activity. A polysaccharide isolated from the bacterium Alteromonas macleodii, collected
27.7 Role of Marine Biotechnology 39
near the Galapagos hydrothermal vents, has been shown to reduce the activity of
intercellular adhesion molecules (ICAMs) associated with the acute stages of skin
inflammation and thereby protect epidermal Langerhans cells. In a clinical setting, it sig-
nificantly reduced irritation and repaired damaged skin. It is currently being marketed
as Abyssine 657 for use in skin creams.
Archaea
Some of the extremophiles found living in and around hydrothermal vents are hyperther-
mophilic archaea. Since they are surviving and growing at temperatures over 100◦ C, they
must have unique enzyme systems that are stable at high temperatures. Thermostable
enzymes have potential uses in research and industrial processes. One commercial prod-
uct, VentTM DNA polymerase, is currently on the market. This enzyme functions at 95◦ C.
It was discovered in Thermococcus litoralis, an archaean isolated from hydrothermal
vent waters. Commercial production is achieved through recombinant techniques in
which the genes of the extremophile are expressed in Escherichia coli.
Fungi
The first true marine drug, the antibiotic cephalosporin C (27.40), was discovered in
the marine fungus Cephalosporium acremonium. It has been in commercial use since
1965 and has proven effective against a variety of bacteria, including penicillin-resistant
strains. The antibiotic effect of this marine fungus was discovered in 1945 as a result of
research conducted on the microbial flora living near a sewage outfall in the Mediter-
ranean Sea. NPI-2358, an analog developed from a marine fungal extract, began Phase
I trials for treatment of solid tumors and lymphomas in 2006. It is a potent selective
vascular disrupting agent, active against multi-drug-resistant human tumor cell lines.
Cephalosporin C
H3N1 H H
S
CHCH2CH2CH2COHN
2OOC
N
O CH2OCOCH3
COOH
Cephalosporin C (27.40)
27.7 ROLE OF MARINE BIOTECHNOLOGY

Innovations in marine biotechnology are likely to improve the scope, scale, and speed of
MNP development. They are also likely to improve mariculture, management of wild fish
stocks, and remediation of marine pollution. New tools represent a blend of molecular
biology and information technology, called genomics and bioinformatics, which can be
performed at the organismal, cellular, and genetic levels.
One of the most promising new directions lies in the use of genetically engineered
bacteria to produce unique biomolecules on a mass scale. The novel metabolisms
exhibited by marine bacteria represent microbial factories for concentrating met-
als, depositing minerals, harnessing solar energy, decomposing sewage and oil, and
exuding anti-biofouling agents. Recombinant techniques, especially those for cloning
metagenomes, should provide the means by which these microbial factories can be
harnessed for human use.
In vitro manipulations, such as cloning, are likely to improve mariculture by enabling
the selection of traits such as increased hardiness to environmental stresses and disease,
as well as fast growth and maturation rates. Molecular markers, such as mitochon-
drial DNA, are now being used to track the populations of commercially important
or endangered species. For example, genetic methods are being used to verify whether
supermarket salmon are farm raised or wild. Evolutionary relationships among species
are being assessed by genetic mapping of DNA. Exposures to toxins (xenobiotics)
induces the production of mixed-function oxygenases, called cytochrome P450, in
plants, bacteria, and animals. These compounds are species specific and can be used
as biomarkers of pollution. They are detected by PCR methods (polymerase chain
reaction).
Advances in biotechnology have also led to the development of biosensors such
as GFP. Other examples are listed in Table 27.9. The gene for production of GFP is
easily inserted into the nuclear materials of plants, bacteria, and animals. Because bio-
luminescence is easily detected at very low levels, expression of the gene for GFP
provides a sensitive marker that can be used to measure cell proliferation, apoptosis,
drug metabolism, and kinase activity (antitumor).
Table 27.9 Biosensors Based on Marine Natural Products.

Chemical Source Target End Point Status
Limulus amebocyte Horseshoe crab, Gram-negative Visual clumping In use
lysate (LAL) Limulus polyphemus endotoxins
Aequorin Jellyfish, Aequorea Ca2+ Bioluminescence In use
victoria
Green fluorescent Jellyfish, Aequorea Tag proteins and Bioluminescence In use
protein (GFP) victoria to follow gene
expression
Lux genes Bacteria, Vibrio Food-borne Bioluminescence In development
fischeri pathogens
Taq and VentTM Extremophiles: DNA Enzymatic activity In use
DNA polymerases Thermus aquaticus
and Prococcus
furiosus
27.7 Role of Marine Biotechnology 41
27.7.1 Final Remarks

MNPs are most properly viewed as catalysts for the discovery and investigation of new
drugs. In other words, we should expect marine chemicals to inspire new drugs rather
than to provide them. Our search for potential drugs from the sea has improved our
understanding of human physiological processes. It could also play an important role in
improving our understanding of marine chemical ecology at the molecular level. This
line of research began with great promise in the 1970s, followed by a period of rapid
discovery of novel compounds. Disappointingly, few have been brought to the com-
mercial market. The 2000s have seen a mini-renaissance in the development of new
marine drugs due to improvements in separation technology, bioassay techniques, and
the application of tools from biotechnology and informatics. Other recent changes that
have improved the prospects of new MNP development have been the establishment
of interdisciplinary research teams and centers and the enhanced information exchange
provided by the Internet. As a result, a respectable number of MNPs are now on the
market with many others in the developmental pipeline. Further successes will depend
on the willingness of companies to invest the significant amounts of time and money
required for drug development.
Unfortunately, equal progress has not been made in the arena of biofouling, where
it was hoped that MNPs would be found that would replace the highly toxic tributyltin
and copper based paints. The only organic antibiofouling product yet to come to market
is SEA-NINETM . This MNP is an isothiazolone that acts as a broad-spectrum antifouling
agent. It biodegrades rapidly after release into seawater or the sediments.
Given the current rapid rate of loss of biodiversity, great concern exists that we
are losing genetic resources before having had a chance to discover their pharmaco-
logical potential. As with the denizens of the tropical rain forests, there is no telling
which species could hold a cure for diseases such as cancer or AIDS. For this reason,
it behooves us to protect these ecosystems.

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CHAPTER

Organic Products from the Sea:

27.2 WHAT ARE MARINE NATURAL PRODUCTS?

27.3 HISTORY OF MARINE ORGANIC PRODUCTS

NVP-LAQ284 psammaplin A, a NSCLC or malignant

Table 27.1 (Continued)

27.4 CHEMICAL ECOLOGY AND STRUCTURE-ACTIVITY

27.5 THE DISCOVERY AND DEVELOPMENT OF MARINE

27.5.1 Marine Bioprospecting

to genetic resources and the provision of assistance in protecting marine biodiver-

27.5.2 Isolation and Screening

Table 27.5 Molecular Targets of Various Bioassays Used in Drug Development.

Pain Ion channels Saxitoxin

27.5.3 Structural Identification and Synthesis

symbionts whose growth is controlled by environmental conditions. This variability

27.5.4 Clinical Trials, Marketing, and Patents

5,000 Compounds Discovery and preclinical testing:

27.6 EXAMPLES OF MARINE NATURAL PRODUCTS

Table 27.6 Biosynthetic Pathways of Natural Products and

Biosynthetic Pathway Structural Class

27.6.1 Macroalgae: Seaweeds

Agarose (27.1) and Agaropectin (27.2)

Partial structure of Carrageenan

Partial structure of Alginic acid

Mannuronic acid L-Guluronic acid

Alginic Acid (27.4)

Macroalgal Natural Products

L-a- Kainic acid

Kainic Acid (27.6)

Fucoidan preparations have anticoagulant activities making them a suitable sub-

a. Ascophyllum nodosum/Fucus vesiculosus/Fucus evanescens b. Ecklonia kurome

As much as 50% of a sponge’s biomass can be composed of bacteria, cyanobacteria,

Spongouridine (27.10) and Spongothymidine (27.11)

Manoalide (27.12) and Halichondrin B (27.13)

Prostaglandin hormones were first discovered in the 1960s. These simple

Gorgonian Mammalian Prostaglandins

Gorgonian (27.15) and Mammalian Prostaglandins (27.16)

Dihydromarthasterone (27.18) and Holothurin (27.19)

A number of steroids isolated from starfish, such as dihydromarthasterone, are toxic

Tyrian purple (27.20)

H 2N Cys25 Ala6 Gly5

Cys16 Cys15 Asp14 Tyr13

Lys24 Thr17 Lys7 Met12

Gly23 Gly18 Cys8 Ser9 Arg10 Leu11

compounds are peptides composed of 10 to 30 amino acids synthesized by the cone

Nereistoxin (27.27) and Padan (27.28)

Anabaseine (27.29) and GTS-21 (27.30)

Ecteinascidin 743 (27.31), Aplidine (27.32), and Staurosporine (27.33)

Table 27.8 Uses of Chitosan.

per year. It is a nontoxic, renewable, and biodegradable resource. Controlled deacetylation

Ciguatoxin (27.35) and Maitotoxin (27.36)

Other Natural Products from Fish

Okadaic acid (27.38)

Cyanobacteria synthesize toxins such as microcystin and BMAA, ␤-N-methyl-

27.7 ROLE OF MARINE BIOTECHNOLOGY

Table 27.9 Biosensors Based on Marine Natural Products.

27.7.1 Final Remarks

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