Marine Pharmacology

1. Dr. Harshad Malve

2. Marine Pharmacology:
Deals with investigation, identification & use of medically
important plants & animals, extracts or substances isolated
from marine organisms
With an estimated 75% of earth’s surface covered by water,
research into the chemistry of marine organisms is
unexplored & represents a vast resource for new drugs to
combat major diseases such as cancer, AIDS or malaria.

3. A wide variety of environments

4. Biodiversity
The oceans are our most biodiverse environment with 34
of the 36 known phyla represented
By comparison, the land has only 17 of the known Phyla!
Genetic diversity translates to chemical diversity =
Promising new drugs

5. Research typically focuses on slow moving or sessile
organisms because of their inherent need for chemical
defenses
Marine pharmacologists work
with extracts or substances
isolated from marine organisms
Cont.

6. Sources of Marine drugs
Majority of marine products have been isolated from:
Sponges
Coelenterates (sea whips, sea fans and soft corals)
 Tunicates
Opisthobranch molluscs (nudibranchs, sea hares, etc.)
Echinoderms (starfish, sea cucumbers, etc.)
Bryozoans (moss animals)
A wide variety of marine microorganisms in their tissues

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8. Development of Marine pharmacology

9. Late 1970s: Marine drug discovery begun, early
investigators demonstrated marine plants & animals were
genetically & biochemically unique
In the 1970's, in a survey of Caribbean invertebrates, the
impressive cytotoxic properties of extracts of mangrove
ascidian Ecteinascidia turbinata were discovered
After 20 years of advancements in chemistry, the active
substances, named the ecteinascidins were isolated in
1990
Cont.

10. Drugs of marine origin:

14. Ziconotide
1st
drug of marine origin which obtained
approval by the FDA on December 31st
2004
A non-opioid, non-NSAID, non-local anesthetic used for
amelioration of chronic pain
Derived from the toxin of cone snail Conus magus
Contains synthetic form of the cone snail peptide ω-
conotoxin
Blocks the N-Type calcium channels on the primary
nociceptive nerves in the spinal cord

15. Used only for “management of severe chronic pain”
Approved for the treatment of chronic pain as a morphine
replacement therapy
It is the most powerful painkiller known to date
Must be administered intrathecally
Common side effects: dizziness, nausea, confusion &
headache
Rare side effects: hallucinations, suicidal thoughts, new or
worsening depression, meningitis and seizures
Cont.

16. Anti-cancer candidates
Ecteinascidin 743
Didemnin B
Dolastatin 10
Halichondrin B
Bryostatin 1
Aplidin (APL)
Kahalalide F (KF)

17. Ecteinascidin 743
A tetrahydroisoquinoline alkaloid produced by the
tunicate Ecteinascidia turbinata
Chemically related to a rare group of microbial
antibiotics, the saframycins
Induces a broad inhibition of activated transcription with
no effect on the constitutive transcription

18. Cont.
Dose limiting toxicities are bone marrow toxicity & fatigue
Does not induce hair loss, mucositis, neurotoxicity or
diarrhoea
European Union & US FDA have granted orphan drug
status for the treatment of patients with advanced soft
tissue sarcoma & ovarian cancer
It is also undergoing clinical trials for the treatment of
breast, prostate, and paediatric sarcomas

19. Didemnin B
Cyclodepsipeptide compounds isolated from a
tunicate (sea-squirt) Trididemhum solidum
1st
isolated in 1978 at the University of Illinois
A strong antiviral agent against both DNA and RNA viruses
like Herpes simplex virus type 1

20. Cont.
A strong immunosuppressant that shows some potential
in skin graft
Showed impressive cytotoxicity against lymphomas
It has completed phase II human clinical trials against
adenocarcinoma of the kidney

21. Dolastin-10
A pentapeptide derived from marine mollusk Dolabella
auricularia with potential antineoplastic activity
Showed outstanding inhibitory effects against several
forms of skin cancers in laboratory studies
Binding to tubulin, it inhibits microtubule assembly,
resulting in the formation of tubulin aggregates &
inhibition of mitosis
Also induces tumor cell apoptosis through a mechanism
involving bcl-2

22. Halichondrin B
This metabolite was discovered in the
marine sponge Halichondria okadai in 1985
Highly potent cytotoxic agent
Eisai 7389 is a synthetic macrocyclic ketone derivative of
the marine natural product Halichondrin B
Entered phase I clinical trials in 2002 & has recently
progressed to phase II clinical trials for the treatment of
advanced and metastatic breast cancer

23. Bryostatin-1
A macrolactone isolated from the
marine bryozoan, Bugula neritina
Modulates cell-signaling enzyme protein kinase C (PKC)
activity
It binds to & inhibits the enzyme resulting in the
inhibition of tumor cell proliferation, the promotion of
tumor cell differentiation & the induction of tumor cell
apoptosis

24. Sensitizes cancer cells to cytotoxic effects of anti-cancer
agents & act synergistically with other chemotherapeutic
agents
Chronic activation of PKC isozymes with bryostatin-1 induces
synthesis of the proteins that are involved in memory
consolidation & therefore, may represent a pharmacological
strategy for antidementic & memory enhancement therapies
Cont.

25. In phase I studies, tumour responses have been observed
in patients with malignant melanoma, lymphoma &
ovarian carcinoma
Dose-limiting toxicity is myalgias
Cont.

26. Aplidin (APL)
A cyclic depsipeptide isolated from the Mediterranean
tunicate Aplidium albicans
Has a potent activity against human MM cell lines &
primary MM tumor cells, including cells resistant to
conventional or novel anti-MM agents
Decreases the secretion of the Vascular Endothelial Growth
factor (VEGF) & expression of the VEGF-r1 receptor

27. Induces apoptosis via activation of Jun N-terminal kinase,
increases intracellular production of ROS & alters
mitochondrial membrane potential
Blocks the cell cycle progression at G1
A remarkable lack of haematological toxicity
6th
October, 2004: Orphan drug status by the US FDA for
the treatment of Multiple Myeloma (MM)
FDA approves production process strategy of Aplidin(R),
as an Anti-tumor agent in 2008
Cont.

28. Kahalalide F (KF)
One of the families of natural depsipeptides isolated from
Hawaiian herbivorous marine mollusk Elysia rufescens
Potent cytotoxic activity in vitro against cell lines from solid
tumors including prostate, breast & colon carcinomas,
neuroblastoma, chondrosarcoma & osteosarcoma
Mechanism of KF action is mostly unknown
Seems to have the lysosomes as the cellular target

29. Cont.
Dose limiting toxicity is acute transaminitis (raised ALT &
AST), with a remarkable absence of bone marrow
suppression, alopecia & other organ toxicities
Phase I trials demonstrated safety of Kahalalide F in
Prostate Cancer patients

30. Amphilactams A–S
Geodin A
Anti-helmintics

31. Amphilactams A–S
Macrocyclic lactone/lactams isolated from the sponge
Amphimedon spp. showed antihelmintic acrivity
comparable to that of existing anthelmintics like levamisole
& closantel
But the mechanism of action of these compounds was not
determined

32. Geodin A
Geodin A Mg salt, was isolated from the sponge Geodia sp.
Mechanism of action of the pure Geodin A was not
explored
It occurs naturally as the Mg salt
It was nematocidal to the nematode Haemonchus
contortus

33. Loloatins A–D
Myticin
Psammaplin A
Anti-bacterials

34. Loloatins A–D
Cyclic decapeptides isolated from a marine bacterium
Exhibited in vitro antimicrobial activity against
methicillin-resistant Staphylococcus aureus, vancomycin-
resistant enterococci & penicillin-resistant Streptococcus
pneumoniae

35. Myticin
Isolated from hemocytes & plasma of the mussel Mytilus
galloprovincialis
Myticins A & B had marked activity against the Gram-
positive strains Micrococcus luteus, Bacillus megaterium &
Enterococcus viridans, other Gram-positive, Gram-
negative bacteria & fungi were unaffected

36. Psammaplin A
A bromotyrosine derivative from the sponge
Psammaplysilla sp. possessed antibacterial activity against
methicillin-resistant Gram-positive Staphylococcus aureus

37. Monoterpenes
Isolated from the marine red alga Plocamium hamatum
One of them was antitubercular towards
Mycobacterium tuberculosis & Mycobacterium avium
Anti-tubercular

38.  Bengazole, bengamide
 Oceanapiside
 Spongistatin I
 Tanikolide
 Theopederins F–J
Anti-fungals

39. The bengazole derivatives & a new bengamide obtained
from the sponge Pachastrissa sp
The bengazole derivatives were observed to be active
against Candida albicans
Oceanapiside, from the sponge Oceanapia phillipensis,
demonstrated antifungal activity against the fluconazole-
resistant yeast Candida glabrata
Cont.

40. Spongistatin 1 isolated from the sponge Hyrtios erecta
demonstrated potent microtubule-severing activity
Mechanism of action of was significantly differerent from
all other antimicrotubule agents
Tanikolide was isolated from the marine cyanobacterium
Lyngbia majuscula
Theopederins F–J from the sponge Theonella swinhoei
Theopederin-F was particularly effective against
Saccharomyces cerevisiae
Cont.

41. 15-a-Methoxy- puupehenol
Isolated from the marine sponge Hyrtios sp. demonstrated
antimalarial activity against chloroquine-susceptible &
chloroquine-resistant strains of P. falciparum
Anti-malarials

42.  Lamellarin α-20-sulfate
 Papuamides A–D
 Polycitone A
 Glycosaminoglycan
 Sulfated β-galactan
 Poly-hydroxysteroids
 Sansalvamide
Anti-virals

43. Alkaloid lamellarin α 20-sulfate in an unidentified ascidian
showed selective in vitro inhibition of HIV integrase
Papuamides A, B, C & D were isolated from the sponges
Theonella mirabilis & Theonella swinhoei
Papuamides A & B inhibited the infection of human T-
lymphoblastoid cells by HIV-1 in vitro
Cont.

44. Polycitone A isolated from the ascidian Polyctor sp., is a
potent inhibitor of the reverse transcriptase of HIV & both
C and B retroviruses, as well as a general inhibitor of
cellular DNA polymerases
As polycitone A is a general inhibitor of DNA polymerases
it cannot serve as an anti-HIV drug but structural
modifications of polycitone A could lead towards the
rational design of new derivatives with anti-HIV reverse
transcriptase activity
Cont.

45. Synthesis of sulfated derivatives of a glycosaminoglycan
isolated from the marine bacterium Pseudomonas sp. & act
against two strains of influenza virus types A & but not B
Introduction of sulfate groups into polysaccharides
containing L-glutamic acid resulted in antiviral activity
against influenza virus type A, but not against type B, this
activity was similar to that of ribavirin
Cont.

46. Sulfated β-galactan from the marine clam Meretrix
petechialis inhibited CD4 HeLa cells from forming syncytia
It was interpreted as probably the result of a “direct
interaction of the polysaccharide with the HIV binding
site at the membrane protein receptor CD4’’
Cont.

47. Maitotoxin
A marine toxin causing ciguatera poisoning
Mechanism of action was similar to U46619 - a
thromboxane A receptor agonist
Anti-plateletes

48. Sulfated fucans:
Derived from brown algae & echinoderm
Highly branched sulfated fucans from brown algae
directly inhibited thrombin,
Linear fucans from echinoderms required the presence of
antithrombin or heparin cofactor II for inhibition of
thrombin
Anti-Coagulants

49. Anti-inflammatory
Africanene,
Cacospongiolide B,
Palinurin, Palinurine A and B
Plakotenin

50. Africanene
Sesquiterpene africanene, isolated from the soft coral
Sinularia leptoclados
It resulted in a more potent reduction of paw volume than
that produced by 100 mg/kg body weight of ibuprofen, in
carrageenan-induced rat edema assay

51. Cacospongionolide B
A novel sesterterpene inhibitor of human synovial
phospholipase A2 isolated from the sponge Fasciospongia
cavernosa
It irreversibly inhibited both secretory PLA2 in vitro and
group II secretory PLA2in vivo

52. Palinurin, Palinurine A & B
Isolated from the marine sponge Ircinia echinata
Palinurin inhibited TXB2& Oxide radicals
Palinurine A and B were relatively ineffective inhibitors of
both TXB2and Oxide radicals

53. Immunosuppressants
Immunosuppresant activity was reported for the
novel glycolipids simplexides, isolated from the
sponge Plakortis simplex
Showed a 43% inhibitory effect on lymph node cell
proliferation

54. Limiting factors for development of
marine drugs
Supply (sustainable, industrially feasible)
Formulation (suitable for clinical use)
Analytical method & preclinical PKs
Pharmacogenetics (metabolic pathway)
Therapeutic index
Toxicities (Xeno)

55. Measures to maintain supply
Controlled & sustainable use of natural resources
Mariculture: Favouring (by farming) the growth of the
organism in its natural milieu
Aquaculture: Culture of the organism under artificial
conditions
Hemisynthesis: use of a parent/related compound as the
starting point followed by a short/industrially effective
synthetic process
Synthesis

56. The available data demonstrates
that:
“The marine ecosystem is not only
productive to discover novel entities
but it is also a tool to identify new
cellular targets for therapeutic
intervention”