Marine Natural
Products
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
1
Importance of marine environment

More than 70 % of the planet’s surface is covered by oceans.

The great biodiversity of marine environment.

More than 300 000 species of plants and animals are described.

Great number of marine organism have no terrestrial
counterparts.
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
2

The very special living condition for marine organisms led
them to adapt different physiological and behavioural
characters which consequently resulted in novel biologically
active molecules.

Sea organisms are mostly unexplored reservoirs of new drugs.

A small number of marine plants, animals, and microbes have
already yielded more than 12000 novel chemicals.

Hundreds of new compounds still being discovered every year
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
3
Phases of work on marine chemistry

In the 1950’s researchers were interested in studying the
marine spines and shells of sea urchins with beautiful colors.

In the 1970’s interest of researchers was attracted to the
halogenated metabolites from red algae.

From the 1980’s till now the marine chemistry was directed by
the currently used sophisticated and smart biological assays.

Interest switched from marine algae to marine invertebrates.
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
4
Problems of marine research
1- The lack of trained personal.
2- Diving hazards.
3- The marine trips are effort, time and money consuming.
4- The time consuming experiments.
5- The scarcity of the starting organism to carry out the complete
study.
6- Recollection problems of the same organisms in the dynamic
environment.
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
5
7- Difficulties in culturing of marine organisms in the lab.
8- Most of the marine secondary metabolites are polar
compounds, so additional difficulties with extraction,
fractionation and separation are faced.
9- The marine organisms are usually associated with parasitic
commensal or symbiotic flora.
10- The lack of folk medicine information or ethnobotanical
documentation.
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
6
The marine biosphere

Marine organisms are classified into
the following phyla:

Monera
Protista
Metazoa
Higher plants



Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
7
Monera

Monerans are one-celled organisms that have no nucleus
or organelles.

Monerans are individual cells that survive on their own.

They do not work together in groups. However, they can
be found in pairs, clumps, or in chains.

The kingdom of Monera is divided into two types or
organisms, bacteria and cyanobacteria.
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
8
Cyanobacteria (blue-green algae )

They make their own food through
the process of photosynthesis.

These cells are found in oceans,
lakes, ponds, swimming pools,
and moist soil.

They are an important food source
for many of the animals in the
water.

They can be found alone, in
colonies, or long thread like
chains.
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
9
Protista



a diverse group of eukaryotic microorganisms.
unicellular, or multicellular without specialized tissues.
They include marine fungi and algae.
1- Marine fungi





live saprophytic on algae, plants or animals.
parasites on shells, crabs, sponges, in the GIT of fishes.
Or symbiotic as in lichens.
Source of antibacterial, antifungal, cytotoxic and antiinflammatory agents.
produce several secondary metabolites e.g. alkaloids,
terpenoids and polyketides.
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
10
2- Algae
are a large and diverse group of simple, typically autotrophic
organisms, ranging from unicellular to multicellular forms.
 They are photosynthetic and simple.
 There are nearly 30,000 algae species.
 They could be divided into the following groups:
1- Red algae (Rhodophyta)
2- Brown algae (Phaeophyta)
3- Green algae (Chlorophyta)
4- Golden brown algae
5- Yellow algae and diatoms (Chrysophyta)
6- Euglenophyta
7- Blue green algae
8- Dinoflagellates (Pyrrophyta)

Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
11
Chlorophyta (green algae)
 About 8000 species.
 Mostly live in fresh water.
 Chlorophyll a and c.
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
12
Rhodophyta (red algae)
 About 5000 – 6000 species.
 95% are marine.
 Chlorophyll a, phycoerythrin.
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
13
Phaeophyta (brown algae)
 About 1500-2000 species.
 99% are marine.
 Chlorophyll a, c and
phycoerythrin.
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
14
Marine animals (Metazoa)








Marine vertebrates and invertebrates were
subjected to chemical study.
These studies covered representative phyla:
Porifera
Cnidaria
Mollusca
Echinodermata
Annelida
Chordata
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
15
Porifera (Sponges ‫)األسفنج‬

Over 9000 known species and
as many species not yet
described.

Aquatic sessile filter feeders.

Simplest animals, multicellular
organisms with specialized
cells found in a various forms,
no organs.

50% of the natural products
reported from marine
invertebrates.

About 2600 metabolites were
isolated.
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
16
Cnidaria








This phylum include: soft and hard corals, gorgonians, sea pens,
jellyfish, sea wasps and sea anemones.
Simple structure: a sac-like body with single opening that functions as
both mouth and anus, one or more circles of tentacles surrounding the
mouth, an internal space called the coelenteron, which serves for
digestion and circulation.
Cnidarians have two body forms:
1- Polyp - stationary, vase-shaped e.g. hydra, coral, sea anemone
2- Medusa - swimming, cup-shaped e.g. jellyfish, portuguese man of
war.
More than 10000 described species.
Only 12% were chemically investigated.
About 1500 metabolites were isolated.
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
17
‫ قنديل البحر‬Jellyfish
Sea pens
‫ شقائق النعمان‬Sea anemones
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
18
Portuguese man of war
‫ المرجان‬Corals
Jellyfish
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
19
Mollusca ‫الرخويات‬



This phylum contains a highly diverse group of animals including
50000 species and 60000 fossil molluscs.
vary greatly in physical appearance, size, and feeding habits.
include snails‫ الحلزون‬, tusk shells, shellfish ‫المحار‬, octopus ‫اإلخطبوط‬,
squids ‫حبار‬, mussels ‫بلح البحر‬
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
20
Mussels ‫بلح البحر‬
Octopus
Squids ‫حبار‬
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
21
Chordata ‫حبليات‬



This phylum includes tunicates and vertebrates.
The most distinctive morphological features of chordates
are the notochord, nerve cord, and visceral clefts and
arches.
About 1500 species of tunicates.
Tunicates
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
22
Echinodermata ‫قنفذيات او شوكيات‬


With 7000 extant and 13000 extinct species.
They are deuterostomes, a deuterostom being an animal in
which the anus is formed from the blastopore during
development and the mouth arises as a secondary invagination.
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
23
Marine secondary
metabolites
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
24
Antitumor and Cytotoxic Agents
1- Didemnins






Group of cyclic depsipeptides isolated from Trididemnum species
(Tunicates).
This tunicate present as a grey-green coating on rocks or coral at
depths of 120 feet.
It is a source of several didemnins like A, B, C, D, E, G, X and Y.
These compounds are cytotoxic, antiviral and immunosuppressive.
The most potent one is didemnin B, which is in phase II clinical
trial as anticancer agent.
It causes inhibiting protein synthesis .
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
25
OH
O
O
O
O
OH O
CH3CH C
C
O
O
O
N
NH
N
O
O
O
N
H
HN
O
N
N
OCH3
Didemnin B
Trididemnum cereum
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
26
2- Dolastatins







Group of cyclic and linear peptides and depsipeptides.
Isolated from the sea hare Dollabella sp. (1 mg per 100 kg).
Dolastatine 10 is the most active one of this series.
The dolastatins are mitotic inhibitors.
They interfere with tubulin formation and thereby disrupt cell
division by mitosis.
Phase II clinical trials of dolastatin 10 in patients with several
types of tumors have been completed.
Later dolastatins 11 and 12 were isolated from cyanobacterium.
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
27
H
N
N
O
N
N
N
O
H
N
OCH3 O
S
OCH3 O
Dolastatine 10
Dolabella sp.
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
28
3- Bryostatins

Group of macrolide lactones isolated primarily from the
bryozoan Bugula neritina, also from sponges and tunicates.

It is believed to be produced by symbiont bacteria to protect
the bryozoan larva from predation or infection.

Bryostatin-1 is the most active one (a potent activator of
protein kinase C).

In vitro trials have shown bryostatins to act synergistically
with other anti-cancer drugs and to modulate protein kinase C
(PKC) activity, with a potent antileukemic effect and action
against lung and prostate tumor cells.
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
29



Bryostatin has appeared very promising enhancing
memory in animal models.
It is now being investigated in human testing, possibly for
treatment of Alzheimer's disease.
Bryostatin is thought to potentiate memory by activating PKC.
Bugula neritina
Bryostatin-1
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
30
4- Alkaloids
A- Ecteinascidins
 They are complicated alkaloids isolated from the tunicate
Ecteinascidia turbinata.
 Ecteinascidin 743 is in clinical trials as anticancer agent.
B- Niphatesine D
 Antineoplastic alkaloid which was isolated from Niphates sp.
(sponge).
C- Clavepictine A and B
 isolated from the tunicate Clavelina picta.
D- Polycarpine
 Dimeric disulphide alkaloid isolated from Polycarpa clavata .
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
31
OCH3
HO
CH3
OAc
H3C
NCH3
S
N
O
O
O
O
CH3O
OH
CH2
Ecteinascidia turbinata
NH
HO
Ecteinascidin 743
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
32
NH2
N
Niphatesine D
Niphates sp. (sponge).
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
33
N
RO
R= Ac. Clavepicitine A
R= H. Clavepicitine B
C6H13
Clavelina picta
NH2
Me
N
OMe
N
S-S
N
MeO
N
Me
Polycarpine
NH2
Polycarpa sp. (Tunicate)
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
34
5- Terpenoids
A- Suberosenone
 Sesquiterpene isolated from the coelenterate Subergorgia
suberosa.
B- Cembranoids
 Isolated from from Sinularia gibberosa e.g. 11, 12epoxycembratrien-15-ol.
C- Sarcoglane
 a diterpene isolated from Sarcophyton glaucum
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
35
Subergorgia suberosa.
Ramzi A. Mothana, PhD
Sinularia gibberosa
PHG220, Marine Natural Products
36
Antiviral active compounds
1- Didemnins

See antitumor and cytotoxic compounds.
2- Avarol and avarone
 Sesquiterpenes attached to quinone or hydroquinone unit



isolated from a sponge, Disidea avara.
These compounds inhibit the human immunodeficiency virus,
(inhibit viral reverse transcriptase activity).
have high therapeutic indices and the ability to cross the
blood–brain barrier.
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
37
O
6`
H
OH
4`
O
Avarone
H
OH
Avarol
Disidea avara
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
38
3- Cyanovirin-N (CV-N)




is a protein produced by the
cyanobacterium that Nostoc
ellipsosporum.
It displays virucidal activity against
several viruses, including HIV.
It Prevents virus-to-cell fusion, viral
entry and infection of cells.
It is of particular interest because of
its relative safety (10,000 times more
toxic to HIV than it is to cells(.
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
39
3- Patellazole B


isolated from the tunicate, Lissoclinum patella
has very potent in vitro activity against herpes simplex viruses.
4- Eudistomins



Group of alkaloids isolated from a tunicate Eudistoma olivaceum.
Have a β-carboline moity.
The most active are eudistomin C,E, K and L
5- Ara-A




a semi-synthetic substance based on the arabinosyl nucleosides,
isolated from the sponge Tethya crypta.
It is arabinosyl adenine (the only compound reported to have
significant therapeutic activity(.
Ara-c is used as antileukemic.
Both act by inhibition of DNA synthesis.
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
40
Eudistoma olivaceum
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
41
Tethya sp.
Ara-A
Tethya crypta
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
42
6- Hennoxazoles



Hennoxazoles A-D were isolated from sponge.
Characterized by the presence of 2 oxazole units.
Hennoxazole A showed an analgesic and a strong anti-HIV-1
activity.
7- Solenolides and Briantheins





They are briarein diterpenoids, containing lacton ring.
Isolated from gorgonian organisms.
The most active is solenolide A.
Briarein diterpenoids have weaker antiviral effect comparing to
Solenolides.
Brianthein Y has also an insecticidal effect.
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
43
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
44
Antibacterial active compounds
1- Squalamine



is the first aminosterol isolated from the dogfish shark Squalus
acanthias (squalidae).
It has potent antimicrobial activity against Staphylococcus
aureus and antitumour properties.
in clinical trials for the treatment of advanced non-small-cell
lung cancer.
2- Cribrostatins


isolated from a blue sponge Cribrochalina sp. and showed
potent antineoplastic and antimicrobial activities.
Cribrostatin 3 has potent inhibitory activity against penicillinresistant Neisseria gonorrheae
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
45
Dogfish shark
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
46
Cribrochalina sp.
Cribrostatin 6
O
O
H 3C
N
C2H5O
CH3
O
Cribrostatine 2
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
47
3- Bromosphaerone


potent antibacterial diterpene, isolated from the red alga
Sphaerococcus coronopifolius.
It shows antibacterial activity against S. aureus.
4- Pestalone


Obtained as a result of a fermentation of marine fungus (the genus
Pestalotia) with marine bacterium.
Pestalone has potent antibiotic activity against methicillin-resistant
S. aureus and vancomycin-resistant Enterococcus faecium.
5- Jorumycin


a dimeric isoquinoline alkaloid that was isolated from the mantle
and mucus of the Pacific nudibranch (Mollusca) Jorunna funebris.
It inhibits the growth of various Gram- positive bacteria.
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
48
Jorumycin
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
49
Antifungal active compounds
1- Jasplakinolide (Jaspamide)


a 19-membered macrocyclic cyclodepsipeptide isolated from a
sponge (a Jaspis sp.)
selective in-vitro antimicrobial activity against Candida albicans.
2- Gambieric acids


are extremely potent antifungal metabolites isolated from a strain of
the epiphytic marine dinoflagellate Gambierdiscus toxicus.
are the first antifungal representatives of the brevetoxin-type (fused
polyether rings) structures, consisting of nine contiguous ether rings
and one isolated tetrahydrofuran .
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
50




Gambieric acid A inhibits the growth of Aspergillus niger at a
concentration of 10 ng/disk.
The potency of gambieric acids exceeds that of amphotericin B
by 2000-fold.
Most antifungal compounds from marine origin are cytotoxic.
Consequently, they have not generally been considered
promising antifungal agents for clinical applications
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
51
brevetoxin-type
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
52
3- Hamacanthin A and Hamacanthin B


Indole alkaloids isolated from Hamacantha sp.
They inhibit the growth of opportunistic fungal pathogens
Hamacanthin A
Hamacanthin B
H
O
H
O
N
2
1
N
2
1
5
N
Br
N
5
N
H
N
Br
Br
H
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
N
N
H
H
Br
53
Antiprotozoal active compounds
1- Cyclic peroxides
 Isolated from sponges (Plakortis sp.) are well known
 Two isolated peroxides are active against Leishmania mexicana.
 The most active cyclic peroxide causes lysis of the cell
membrane after 24h.
 however, less effective than ketoconazole.
2- Manzamine A
 an alkaloid displays 70% inhibition of the T. gondii parasite, at
0·054 g/mL concentration, without cell toxic effects.
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
54
Anti-inflammatory Agents
1- Manoalide
 Isolated from Luffariella variabilis
 Irreversibly inhibits phospholipase A2
2- Dysidine
 Isolated from Dysidea sp.
 Exerts higher potency and selectivity toward phospholipase A2
than manoalide.
3- Cordiachromen A
 Isolated from Aplidium multiplicatum
 Strong anti-inflammatory effect similar to that of indomethacin
 It inhibits prostacyclin synthesis (inhibition of cyclooxygenase
pathway.
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
55
O
HO
H
H
SO3H
NH
O
Dysidine
O
HO
O
O
HO
HO
Cordiachromen A
O
Manoalide
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
56
OH
O
OH
H
O
OH
4- Pseudopterosins



Pseudopterosins isolated
from Pseudopterogorgia
bipinnata.
They inhibit PGs and LTs
biosynthesis
It exhibited potent antiinflammatory and analgesic
activities
OH
Pseudopterosin A
OH
OAc
O
O
OH
H
OH
Pseudopterosin C
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
57
Pseudopterogorgia sp.
Ramzi A. Mothana, PhD
PHG220, Marine Natural Products
58