BIOACTIVE COMPOUNDS

FROM MARINE ORGANISMS

Marine bioactive compounds are organic compounds
produced by microbes, sponges, gorgonians, soft and
hard corals seaweeds, and other marine organisms.
These products are the current interest of industry for
new drugs and chemicals.
Marine microorganisms form highly specific and
symbiotic relationships with filter-feeding organisms
like sponges, alcyonarians, ascidians and marine
plants.
The host organism synthesizes these compounds as
non-primary or secondary metabolites to protect
themselves and to maintain homeostasis in their
environment.
 A diverse array of bioactive compounds can be isolated
from the extracts of marine organisms.
Many of them have novel chemical structures which
may lead to the development of entirely new drugs
and therapeutic agents.
Anti-cancer agents have been isolated from algae,
sponges, jellyfish, corals, shark cartilage and shellfish.
The Pacific oyster contains a substance which may help
diabetics by promoting the secretion of insulin.
Chemicals found in sponges may be used to treat
yeast and fungi.
A poison emitted by the cone snail has been found to
prevent brain damage in animals after a head injury or
stroke, and offers great promise in future applications
in humans.
1. Marine bacteria
It has been demonstrated that marine bacteria produce
anti-microbial substances.
The first documented identification of a bioactive marine
bacterial metabolite was the highly brominated pyrrole
antibiotic, isolated from a bacterium obtained from the
surface of the Caribbean Sea grass Thalassia.
This metabolite was identified by x-ray crystallographic
methods, which composed of more than 70% bromine by
weight.
The metabolite exhibited impressive in vitro antibiotic
properties against Gram-positive bacteria, with minimum
inhibitory concentration (MIC) ranging from 0.0063 to 0.2
g/ml.
However, it was inactive for Gram-negative bacteria and
animal assays.
 It is becoming abundantly clear that bacteria form
highly specific, symbiotic relationships with marine
plants and animals.
Experience in this area arose from a study of the
pathogen resistance of the estuarine shrimp
Palaemon macrodactylus.
The eggs of P. dactylus possess significant bacterial
epibionts, which, when removed by treatment with
antibiotics, leads to the rapid infestation of the eggs
by pathogenic fungi, especially of Lagenidium
callinectes.
It could be due to the anti-fungal agents produced
by bacteria.
2. Marine fungi
Although terrestrial fungi have represented a major
biomedicinal resource (e.g., penicillin from
Penicillium), studies to develop the biomedicinal
potential of marine fungi were less.
The isolation of a small lactone, leptosphaerin from
Leptosphaeria oraemaris demonstrated that marine
fungi may form important resource for unique
metabolites.
Later, the useful chemical, Gliovictin was isolated from
marine fungus, Asteromyces cruciatus.
Since then more than twenty useful bioactive
compounds have been derived from marine fungi.
3. Marine microalgae
Marine microalgae are relatively unexploited but rich
resources for bioactive compounds.
Toxins initially isolated from fish or shellfish were
found to originate from microalgae, especially
dinoflagellates.
These toxins are useful tools to investigate the
structure and function of ion channels on cell
membranes or to elucidate the mechanism of tumor
promotion based on their specific inhibitory action
against protein phosphatases.
The number of antifungal or antitumoral substances of
microalgal origin is rapidly increasing.
 More importantly, structural similarities have been
found between many bioactives found in marine
invertebrates and those in freshwater blue-green
algae.
The similarities point to a great potential of marine
blue-greens, the least explored resource, for
producing bioactive compounds of medicinal value.
Microalgae are significant resource for bioactive
metabolites, particularly cytotoxic agents with
applications in cancer chemotherapy.
From the marine microalgae such as from the blooms
of Phaeocystis sp., antibiotic substances were listed.
P. pouchetii is reported to produce chemicals such as
Acrylic acid, which constitutes about 7.0% of the dry
weight.
 The antibiotic substances thus produced are
transferred throughout the food chain and found
in the digestive tract of Antartic penguins.
Production of carotene and vitamins by the
halotolerant alga Dunaliella sp., is documented.
Microalgae produce incredibly potent alkaloidal
neurotoxins such as saxitoxin and polyketide
neurotoxins such as the brevetoxins.
4. Marine macroalgae
Of the total marine algae so far evaluated, about
25% showed one or the other biological activity.
The metabolites of green algae were reported to
contain 1,4 diacetoxic butadiene moiety, which
exhibited icthyotoxic property.
Among the red algae, halogenated lipids have
been isolated, particularly from the Laurencia
sp.
The rare chemical prostaglandin was also
reported to occur in Gracilaria pichenoids.
 Ulva meal supplementation was found to provide
disease resistance to red sea bream in Japan.
Similar results were also reported from Japan on the
use of Ulva meal supplementation towards disease
resistance and high growth rate in black sea bream.
The polysaccharide fractions from marine algae,
Porphyra yezoensis was found to stimulate the in vivo
and in vitro murine phagocytic function.
The purified fractions gave stronger phagocytic
activity. Some of the macro algal crude extracts
indicated their potential therapeutic nature when
challenged with potential pathogens among fish and
shellfish.
5. Marine sponges
Chemicals found in sponges may be used to treat yeast and
fungi.
The wider biosynthetic capability of sponges could be
attributed to their biological association with other
symbionts.
About 38% of the sponge body comprises of microorganisms.
A wide variety of secondary metabolites were isolated from
sponges and these have been associated with antibacterial,
antimicrobial, antiviral, antifouling, HIV-protease inhibitory,
HIV reverse transcriptase inhibitory, immuno-suppressent and
cytotoxic activities.
In addition to potential anticancer applications, the bioactive
compounds of sponges have a myriad of activities ranging
from antibiotic activity including anticoagulant, antithrombin,
anti-inflammatory, as well as imunomodulatory activities.
 The fact that the psammaplins have been isolated from
a diversity of sponge sources and that brominated
aromatic amino acid derivatives are common in marine
bacteria suggests that these metabolites may actually
derive from biosynthetic pathways of microorganisms
living in association with sponges.
Presence of specific symbiont morphologies of bacteria
within specific sponges has been reported.
These specific bacteria, which live symbiotically with
sponges, passed through their feeding chambers
without being digested.
This suggested some sort of encapsulation or
recognition process.
 In the demosponge, Halichondria panicea, an association with
the microbe Pseudomonas insolita was suggested to be lectin-
based.
In the case of halichondrin, the exciting anticancer potential of
this sponge metabolite has fueled an innovative chemical
synthesis approach.
Marine animals have yielded cardiovascular-active substances,
and these include histamine and N-methylated histamines of
sponges, viz. Verongia fistularis; asystolic nucleosides from the
sponge, Dasychalina cyathina; and the nucleoside,
spongosine, isolated from Cryptotethya crypta.
6. Sea Anemones
In a 1977 conference on Drugs and Food from the Sea :
Myth or Reality, researchers described cardiotonic
polypeptides from sea anemones .
The sea anemone, Anemonia sulcata is a well-known
natural source of supply of biologically active polypeptides.
So far, five toxins, ATX I, II, III, IV and AS V, several polyvalent
protease inhibitors, an elastase inhibitor, two blood
pressure-depressive polypeptides have been isolated from
it.
The sea anemone toxins (especially toxin II of A. sulcata,
ATX II) are very important tools in neurophysiological and
pharmacological research.
7. Ascidians
Ascidians synthesize bioactive substances which are
cytotoxic.
8. Tunicates
Rinehart et al. (1981) have described antiviral and
antitumor depsipeptides from a Caribbean tunicate.
The tunicate of the Trididemnum genus, when extracted
with methanol-tolulene (3:1), showed activity against
herpes simplex virus, type I, grown in CV-1 cells (monkey
kidney tissue), indicating that the extract inhibited the
growth of the virus.
This antiviral activity may also involve antitumor activity.
When tested against other viruses, essentially all extracts
of the tunicate collected at a number of sites showed
activity in inhibiting both RNA and DNA viruses.
The suggestion that the extracts might also have antitumor
properties was evidenced from their high potency against
L1210 murine leukemic cells.
 Didemnin B, a cyclic antiproliferative
depsipeptide isolated from the Caribbean
tunicate Trididemnum solidum, was the first
marine natural product to enter clinical trial as
an antitumor agent.
It showed antitumor activity against a variety of
models and has been investigated in phase II
clinical trials for the treatment of breast,
ovarian, cervical, myeloma, and lung cancers.
Didemnin B inhibits the synthesis of RNA, DNA,
and proteins and binds noncompetitively to
palmitoyl protein thioesterase.
9. Sea Hares
In the early 1970s, the extremely potent anticancer
properties were reported from the extracts of sea
hare Dolabella auricularia.
However, due to the vanishingly small abundance of
the active principle (1.0 mg/100 kg of collected
organism), the structure elucidation of dolastatin 10
took nearly 15 years to complete.
The low concentrations of dolastatin 10 in sea hares
implicates a cyanobacterial diet as the origin of this
bioactive secondary metabolite, and this was
subsequently confirmed by direct isolation of
dolastatin 10 from field collections of the marine
cyanobacterium Symploca.
 Marine Toxins
A toxin is a substance possessing a specific functional
group arranged in the molecule (s) and showing strong
physiological activity.
A toxin has the potential to be applied as a drug or
pharmacological reagent.
Even if direct use as a drug is not feasible because of
potent of harmful side effects, the toxin can serve as a
model for synthesis or improvement of other drugs.
Many attempts have been made to develop useful
drugs from the sea by screening for anticarcinogenic,
antibiotic, growth-promoting (or inhibiting), hemolytic,
analgetic, antispasmodic, hypotensive, and
hypertensive agents.
 Tetrodotoxin, the main action of which is paralysis of
peripheral nerves, is a valuable pharmacological reagent.
Because it inhibits specifically the sodium permeability of
nerve membranes, it has been valuable for elucidating the
excitation mechanism.
Insecticide developed from nereistoxin are widely
marketed.
Fishermen are familiar with the fact that flies die when
they come into contact with the dead marine annelid,
Lumbrinereis (Lumbriconereis) brevicirra, commonly used
as bait.
A new insecticide was developed from nereistoxin that was
active against the rice stem borer and other insect pests, it
does not appear to be toxic to warm blooded animals, and
resistant strains of insects do not readily develop.
 Marine toxins show great promise not only as
pharmacological reagents, but also as models for the
development of new synthetic chemicals.
Recently ciguatoxin, palytoxin and halitoxin have also
been investigated and provide interesting new
information.
Ciguatera is a human disease caused by the ingestion
of a wide variety of coral reef fishes that contain toxins
accumulated via the marine food web.
The principal toxin of ciguatera poisoning is a heat-
stable, lipid-soluble compound named ciguatoxin.
Origin of the toxin is not yet fully understood but may
be derived by the fish from ingestion of toxic tropical
red tide dinoflagellates such as Pyrodinium
bahamense.
 Halitoxin, a toxic complex of several marine
sponges of the genus Haliclona, has been
isolated, partially purified, spectrally
characterized, and chemically degraded,
yielding a proposed chemical structure for the
toxin.
The toxin has proved to be a complex mixture
of high molecular weight and toxic pyridinium
salts, and can be isolated from the sponges,
Haliclona rubens, H. viridis, and H. erina.
The sponge extracts are toxic for fish and
mice.
 Lophotoxin, a new neuromuscular toxin
isolated from several Pacific gorgonians of the
genus Lophogorgia, has been isolated and
purified.
Lophotoxin inhibits nerve-stimulated
contraction without affecting contraction
evoked by direct electrical stimulation of the
muscle.
The data suggest that epoxylactone and
furanoaldehyde groups may be responsible for
the potent biological properties of lophotoxin.
 Palytoxin, an extremely poisonous, water-
soluble substance from marine coelenterates
belonging to the genus Palythoa.
Palytoxin influences calcium and potassium
ion transport in nerves and the heart.
Animals undergo paralysis and heart failure.
Palytoxin is synthesized by a marine Vibrio
sp. growing symbiotically with the
coelenterate Palythoa and apparently related
to Vibrio cholerae.
 Several marine organisms have provided
useful drugs : liver oil from some fish provides
excellent sources of vitamins A and D.
Insulin has been extracted from whales and
tuna fish; and the red alga, Digenia simplex,
has long been used as an anthelminthic.
Thank you