Marine Pharmacognosy

 CHAPTER 28 

Marine Pharmacognosy

INTRODUCTION

• Marine pharmacognosy is a sub-branch of pharmacognosy, which is mainly concerned with the naturally occurring substances of medicinal value from marine source. It is not a new area for pharmacognosy; even the early civilizations of Greece, Japan, China and India have explored marine life as a source of drugs. In the western medicine agar, alginic acid, carrageenan, protamine sulphate, spermaceti and cod and halibut liver oils are the established marine medicinal products

• The oceans cover more than 70% of the earth’s surface and contain over 200,000 invertebrates and algal species. Macroalgae or seaweeds have been used as crude drugs in the treatment of iodine deficiency states such as goitre, etc. Some seaweed have also been utilized as sources of additional vitamins and in the treatment of anaemia during pregnancy. Marine products have also been used for the treatment of various intestinal disorders as vermifuges, hypochloesterolaemic and hypoglycemic agent, e.g. Cystoseria barbata, Sargassum confusam and Jania rubens.

• Seaweeds have also been employed as dressing materials, ointments and in gynaecology. For example, Porphyra atropurpurea have been used in Hawaii to dress wounds and burns; Durvillaea antractica to treat scabies in New Zealand. Prepared, sterilized stripes of Laminaria digitala in conjunction with prostaglandins have been used to dilate the cervix, as the strips swell up to several times to their original diameter when moistened.

• During the last 30–40 years numerous novel compounds have been isolated from marine organisms having biological activities such as antibacterial, antiviral, antitumour, antiparasitic, anticoagulants, antimicrobial, antiinflammatory and cardiovascular active products.

• Marine flora and fauna play a significant role as a source of new molecular entity. The oceans of the world contain over five million species in about 30 phyla. Because of the diversities of marine organism and habitats, marine natural products enclose a wide variety of chemical classes, including terpenes, shikimates, polyketides, acetogenins,

• peptides, alkaloids of varying structures and a multitude of compounds of mixed biosynthesis.

• While terrestrial sources have yielded numerous drugs, marine natural products represent a relatively untapped resource for new drug development. The marine environment may contain over 80% of the world’s plant and animal species. During the past 30–40 years, numerous novel compounds have been isolated from marine organisms and many of these have been reported to have biological activities, some of which are of interest from the point of view of potential drug development. On the other hand, some of the compounds pose potential risk to human health. In this latter category are the paralytic or diarrhoetic and amnesic shellfish toxins. The former can be fatal, but the latter, although producing very unpleasant effects, are not fatal. Both paralytic and diarrhoetic shellfish toxins are produced by dinoflagellates, while amnesic shellfish, poisoning result from the ingestion of shellfish contaminated with diatoms. The ingestion of other marine organisms, which can also lead to serious poisoning, include the potent neurotoxin, tetrodotoxin, resulting from eating pufferfish and ciguatoxin, associated with ingestion of tropical fish which have fed on the dinoflagellate, Gambierdiscus toxicus. 

MARINE ORGANISMS AS POTENTIAL SOURCE OF DRUGS

• Knowledge of biological activities and/or chemical constituents of marine organisms is important not only for the discovery of new therapeutic agents but such information may also be of immense value in exploring, new sources of economic materials, precursors for the synthesis of complex chemical substances and compounds of novel chemical structure, thereby prompting the chemist for the synthesis of a series of modified compounds of therapeutically importance. Thus, in recent years, considerable importance is attached to the discovery of new biodynamic agents from marine source to search new source of drugs from sea.

• A survey of literature indicated that extracts from marine organisms had been evaluated for various biological activities. This has led to the isolation of substances possessing antimicrobial, antibiotic, antiviral, anticancer, cardioactive, anti-inflammatory, anthelmintic, anticoagulant neurophysiological and insecticidal activities.

• Although, numerous compounds have been isolated from marine organisms and the biological activities attributed too many of them; but still very few of them have been marketed or are under development. There are number of reasons that are why more number of compounds originating from marine plants and animals has not been developed. There is no doubt that much of the work undertaken in the 1960s, 1970s and probably the early 1980s was driven by an interest in the chemistry of new compounds rather than in their biological activities. The earlier studies on chemistry of marine natural products were limited to the isolation, structure elucidation and phylogenetic relationship of specific substances, such as quinonoid pigments and sterols. Now this field attracted the attention of not only the natural product chemists but also those of marine biologist, biochemist, pharmacologist, etc. The invention of the aqualung and the advent of new technology in the past few decades led to the awareness that the oceans may be a new frontier of biomedical research, as it has vast resources for the discovery of marine-derived medicine. Increasing sophistication of the tools available to explore the deep sea has expanded the habitats, which can be sampled and has greatly improved the opportunities for discovery of novel metabolites.

• Much of the earlier work limited the biological testing to antimicrobial activity, but this was often extended later to testing for cytotoxic properties, which may provide useful leads for anticancer drugs. This latter area is one that most of the compounds in various stages of clinical trials are located. Screening for other activities has of course, also been undertaken, for example, for antiviral, antiinflammatory, anticoagulant, antiparasitic and prostaglandins.

• Many of the marine compounds have shown promising biological properties but have complicated chemical structures, the synthesis of which would be hard andexpensive. These organisms are valuable as source of new biologically active chemical structures, but unless either the compounds or a derivative of them can be readily synthesized, they are of little commercial interest to the pharmaceutical industry.

ANTIVIRAL AGENTS

Ara-A

Ara-A is a semisynthetic antiviral agent based on the arabinosyl nucleoside isolated from the marine sponge Tethya crypta. The compound shows a prominent therapeutic activity

Eudistomins

Eudistomins are the β-caboline derivatives which are isolated from sponges and gorgonians Eudistoma olivaceum, family Polycitoridae. These compounds are also found in tunicates. Eudistomin compounds can be classified into four groups, i.e. pyrrolyl substituted, pyrrolinyl-substituted, unsubstituted and tetrahydro-β-carboline derivatives with a 1,3,7- oxathiazepine ring.

Didemnins

Didemnin compounds are the promising antiviral and antitumour agents isolated from Trididemnum Spp. family Didemnidae. A compound Didemnin B is found to be a potential antitumour agent during its clinical trials.

Avarol and Avarones

These two sesquiterpene benzenoids are derived from the sponge Disidea avara. It has exhibited strong anti-HIV activity against the human immunodeficiency virus (HIV). It shows the greater promises in the treatment of AIDS.

Patellazole B

Patellazole B is a complex derivative isolated from the ascidian Lissoclinum patella. It has shown the potent activity against Herpes simplex virus

Fucoidan

Fucoidan, a sulphated polysaccharide compound extracted from brown algae Laminaria has shown the activity against HIV and Herpes simplex viruses.

ANTIMICROBIAL AGENTS

• A large variety of antimicrobial agents are produced by number of marine organisms, such as sponges, algae, gorgonian corals, annelids, etc., and many of them are active against gram +ve and gram –ve microorganisms, protozoal and fungal strains. Various antimicrobial, antibacterial, antifungal and antiprotozoal agents from marine sources are given below. A list of antibiotics agents derived from marine organisms have also been enumerated.

 ANTIPARASITIC AGENTS

• Various compounds isolated from the marine organisms have demonstrated remarkable antiparasitic activities. Some of the important agents have been listed below

α-Kainic Acid

α-Kainic acid isolated from the red algae, Digenia simplex shows the broad spectrum anthelmintic activity against the parasitic round worms, tape worms and whip worms. Dried powder of D. simplex has been widely used for the treatment of ascariasis. A Japanese pharmaceutical company, Takeda Pharmaceuticals, produces various preparations of this drug

Domoic Acid

Domoic acid is a compound chemically related to kainic acid. It has been isolated from red algae Chondria armata and Alsidium corallinum. It has shown prominent anthelmintic activities.

Laminine

Laminine is a methylated lysine derivative found in the marine red algae of the order Laminariales as well as in brown algae. Laminarine also shows the hypotensive andsmooth muscle relaxant activities, along with its potential antiparasitic activity.

 Bengamide F

Bengamide F is the recently isolated and characterized compound from marine sponge. It has demonstrated a remarkable antiparasitic activity during in vitro studies.

ANTICANCER AGENTS

Several compounds with anticancer and cytotoxic activities have been isolated and characterized from various marine organisms, such as marine sponges, gorgonian corals, sea algae, sea hares and sea cucumbers. One of the most prominent synthetic anticancer agents is cytosine arabinoside, also known as Ara-c. It originates from the natural marine substance spongothymidine isolated from Caribbean sponge (Cryptotethya crypta). It is marketed under the trade name Cytosar by Upjohn pharmaceutical company for the treatment of acute myelogenous leukaemia and human acut

Cucumechinoside F

• Cucumechinoside F is a complex tetracyclic triterpenic glycoside obtained from sea cucumber. It has been reported to have a prominent antiprotozoal activityleukaemia. Ara-c is a potent inhibitor of the tumours in cases of sarcoma-180, Erlich carcinoma and L-1210 leukaemia in mice. Ara-A adenine arabinoside, another synthetic analog developed on the prototype of spongothymidine is effective for the treatment of herpes encephalitis. The other compounds isolated from the above Caribbean sponge are spongosine and spongouridine.

Bryostatin I

Isolated from Bugula neritina a bryozoal marine organism showed highly potent antineoplastic activity in an extremely low dose level.

ANTISPASMODIC AGENTS

Agelasidine A

A sesquiterpene derivative isolated from Okinawa Sea sponge Agelas Spp. has demonstrated very good antispasmodic activity in animal models. Agelasidine A is the first marine natural products containing guanine and sulfone units.

CARDIOVASCULAR AGENTS

• Several cardiovascular agents have been isolated and characterized from marine organisms. Their chemical nature ranging from steroidal compounds to polypeptide of 49 amino acids residues have been isolated from the sea anemone Arthropleura xanthogrammica. It is a highly potent heart stimulant with about 5,000 times more activity than cardiac glycosides.

Eledoisin

• Eledoisin, a peptide compound has been isolated from posterior salivary glands of Cephalopod Eledone moschataand other related species. It has shown potent hypotensive and vasodilatory activity. It is found to be about 50 times more potent than acetyl choline, histamine or bradikinin in provoking hypotension.

Octopamine

• D(-) Octopamine a simple phenolic derivative isolated from salivary glands of Octopus vulgaris, O. macropus and Eledone moschata has shown remarkable cardiotonic activity

• A toxic compound tetramine isolated from the salivary glands of Neptunea antiqua showed curare like effect in mammals. A basic amino acid laminine isolated from red algae Laminaria angustata has also shown hypotensive activity similar to that of choline

ANTIINFLAMMATORY AGENTS

Marine organisms have shown the presence of novel antiinflammatory agents. A series of bio-indol derivatives isolated from marine cyanobacterium Rivularia firma has shown potential antiinflammatory activity in the models of carrageenan-induced rat paw oedema. In another study, the butanolide derivatives obtained from Euplexaura flava have demonstrated a significant antiinflammatory effect in a low dose of 100 ug/ml. The sulphated polysaccharide carrageenan isolated from Irish moss, Chondrus crispus, a red algae is used as a phlogistic agent for inducing inflammation in the rat paw oedema model for the study of antiinflammatory activity

INSECTICIDES

Nereistoxin an insecticidal compound has been isolated from the marine annelid Lumbriconereis heteropoda. Many semisynthetic and synthetic analogs have been produced on the structural model of nereistoxin. One of the derivative named as cartap is used as an insecticide in Japan.

ANTICOAGULANTS

• Anticoagulants reported from the marine sources are mostly polysaccharide derivatives obtained from marine algae. Carrageenans from Condrus crispus and galactan sulphuric acid from Iridaea laminarioides have shown anticoagulant effect through inactivation of thrombin.

• Fucoidin isolated from the brown algae Fucus vesiculosus has shown a very good anticoagulant activity. The antithrombin effect of fucoidin is mediated through heparin cofactor II. 

 PROSTAGLANDINS

Prostaglandins constitute a class of natural products with variety of therapeutic activities. Varieties of these substances are found in marine algae and corals. Soft coral, Plexaura homomalla is regarded as a rich source of these compounds, 15 epi-PGA2 found in the form of its acetate and methyl ester derivative.

PGE2 and PGF2a types of prostaglandins have been isolated from the red algae Gracilaria lichenoides. PGE2 have also been derived from G. verucossa.

Red sea soft coral, Lobiphyton depressum, has been shown to contain four PGF derivatives (15s)-PGF2α 11-acetate methyl ether. Recently Corey and coworkers reported the enzymatic transformation of arachidonic acid using cell-free extract of Clavularia viridis to produce a new prostaglandin derivative I (Prostanoide).

MARINE TOXINS

Many marine organisms produce potentially toxic compounds which may work for their safety and protect them from predators. These toxins may pose potential hazards to human health. Many of these toxins had also shown remarkable biological activities in comparatively lower doses. Some of these marine toxins are discussed below:

Tetrodotoxin

Tetrodotoxins is a potent neurotoxin produced by the pufferfish of family Tetraodontidae. It is present in other animals including Gobius crinigar, Taricha torosa, Atelopus chiriquensicmarine crabs and also produced by marine bacteria. This dangerous toxin shows the cardiovascular and neurophysiological activity in experimental animals. Tetrodotoxin containing puffer fish is considered as a delicacy in Japan, but great care is exercised to avoid the toxin during its preparation for culinary purpose. 

Saxitoxin

Saxitoxin is a purine skeleton containing toxic compound produced by the butter clam Saxidomus giganteus and California mussel Mytilus californianus. It is also found in two toxic species of mollusc, Zolimus aeneus and Platipodia granulosa. Saxitoxin is identical with toxin isolated from the dinoflagellate Gonyaulax calenella upon which the butter clam feeds. In lower doses this toxin produces a marked hypotensive effect.

Ciguatoxin

Ciguatoxin is the poisonous compound found in the dinoflagellate Gambierdiscus toxicus. In many cases it is responsible for ciguatera fish poisoning associated with the utilization of tropical fish resources. Ciguatoxin shows the cardiovascular and neurophysiological properties. Another toxin, Maitotoxin, present in G. toxicus is found to be powerful calcium channel activator in a very low dose of pico- to nano-molar range.

Holothurin A

Holothurin A is a toxic saponin isolated from the sea cucumber of Holothurian group Helix pomatia. It is recognized as a mixture of triterpenic aglycones which are linked to four sugar molecules and a molecule of sulphuric acid as a sodium salt. It has shown haemolytic and neurotoxic properties.

Aplysins

Aplysins is a group of toxic compounds isolated from Mediterranean Sea hares Aplysia depilans. Aplysins contains an unpleasant, colourless fluid secreted by the skin. These are the white viscous liquid by opaline gland and purple secretion from another gland present in sea hares. Aplysins causes paralysis when injected into cold-blooded animals.

Lophotoxin

Lophotoxin is a diterpene lactone present in the gorgonian corals of the genus Lophogorgia. It produces an irreversible postsynaptic blockage at neuromuscular junction.

Lyngbyatoxin

Lyngbyatoxin is an indol group of alkaloid produced by the marine cyanobacterium Lyngbya majuscula. It is responsible for the contact dermatitis known as ‘sweemers itch’ in the humans. Some other organisms of the same species L. majuscula have been found to produce totally unrelated skin irritant; debromoaplysiatoxin winch also demonstrates antineoplastic activity

CONCLUSION

The greater part of the earth surface is covered by seas and ocean, which contains about 500,000 species of marine organisms. Since the natural products chemists diverted their attention to exploit the vast resources of marine flora and animal world, numerous novel compounds have been isolated from these marine organisms during the second half of the twentieth century. Many of these compounds have shown

 pronounced biological activity. However, the compounds which have failed to show the activities for which those were assayed cannot be regarded as not having other biological activities. Many of these compounds might show some other activities if studied extensively during the course of time. Although the impact of marine natural products is presently lesser on the pharmaceutical industry, it may come forward in a big way to provide new lead compounds for the development of potential therapeutically active compounds.