Marine Pharmacology

Ocean of opportunities

Dr Panini Patankar
Guide: Dr Shirish Joshi
 Why New Sources?

• Overburden on existing resources for the drug

• 68 % of anti-microbials and 63 % of anti-cancer drugs are

naturally derived

• Drug manufacturers always on lookout for new resources

• Increased contempory tendency for use of natural

products in medicine
Malve H. Exploring the ocean for new drug developments: Marine pharmacology. Journal of Pharmacy
and Bioallied Sciences. 2016;8(2):83.
Why
Oceans?
• Molecules of marine origin can be accepted by humans with

minimal manipulation 1

• Exceptional store-house of novel bio-active natural products

with unique structural and chemical features

• High genetic diversity and chemical diversity as 32 out of 36

phyla known, embodied in marine environment

• Over 3000 molecules with active properties are unique to

marine life
1. Vignesh S, Raja A, James RA. Marine drugs: Implication and future studies. Int J Pharmacol. 2011;7:22–30.
 Definition

It is a branch of pharmacology dealing

with investigation, identification and
use of medically important plants and
animals, extracts or substances
isolated from marine organisms

Singh K, Kanase H. Marine pharmacology: potential, challenges, and future in India. Journal of Medical
Sciences. 2018;38(2):49.
Focus of Marine Pharmacology
• Slow moving or sessile
organisms as they have
evolutionary need for
chemical defences
• Work on extracts or
substances isolated from
such organisms
Malve H. Exploring the ocean for new drug developments: Marine pharmacology. Journal of
Pharmacy and Bioallied Sciences. 2016;8(2):83.
 Timeline

1950: Spongiosine, first 1990: Active

biologically active marine substances called
natural product by Ecteinascindins were
2010s: 5
Bergmann isolated
drugs
approved
by US FDA
and many
drugs in
pipeline
1970: Discovery of 31st December 2004:
cytotoxic properties First drug of marine
of Ecteinascidia origin approved by US
turbinata FDA
 Sources of Marine Drugs
1) Sponges (Most Common)

2) Coelenterates (sea whips, sea fans)

3) Tunicates
4) Ophisthobranch Molluscs (Sea hares)

5) Echinoderms (Star fish & sea-

cucumber)
6) Bryozoans (Moss animals)
 Sources of Marine Drugs

Sea whip Sea Fan Tunicates

Sea Hare Star Fish Sea Cucumber

 Sources of Marine Drugs

• Generally secondary metabolites not generated by

biological or regular metabolic pathways

• Have no primary functions associated with growth,

development and propagation of species

Martins A, Vieira H, Gaspar H, Santos S. Marketed marine natural products in the pharmaceutical and
cosmeceutical industries: Tips for success. Mar Drugs. 2014;12:1066–101.
 Antibacterial
• Eicosapentaenoic acid is isolated from

diatom Phaeodactylium tricornutum

• Shown activity against multitude of

Gram positive and negative bacteria

• Also shown activity against multi-drug

resistant Staphylococcus aureus

Desbois AP, Mearns-Spragg A, Smith VJ. A fatty acid from the diatom Phaeodactylum tricornutum is antibacterial
against diverse bacteria including multi-resistant Staphylococcus aureus (MRSA) Mar Biotechnol (NY) 2009;11:45–52.
 Anti-Inflammatory
Mediterranean sponge species

(Spongia officinalis) extracts and

other related species have shown

anti-inflammatory properties in vivo

study on rat model of carrageenan

induced rat paw oedema

Dellai A, Laroche-Clary A, Mhadhebi L, Robert J, Bouraoui A. Anti-inflammatory and antiproliferative activities of crude
extract and its fractions of the defensive secretion from the mediterranean sponge. Spongia officinalis. Drug Dev
Res. 2010;71:412–8.
 Neuro-Protective
• Extracts of South Indian Green

seaweed Ulva reticulata have shown

neuroprotective action with efficacy

comparable to currently approved

drugs for Alzheimer’s disease

• Act by inhibition of acetyl-and butyryl-

cholinesterases
Russo P, Kisialiou A, Lamonaca P, Moroni R, Prinzi G, Fini M. New Drugs from Marine Organisms in Alzheimer’s
Disease. Marine Drugs. 2015;14(1):5.
 Anti-parasitic
• Extract of Tunisian sponge
(Sarcotragus sp.) prepared in
dichloromethane has shown anti-
leishmanial activity
• In vitro morphological alterations in
promastigotes of leishmania major were
demonstrated
Ben Kahla-Nakbi A, Haouas N, El Ouaer A, Guerbej H, Ben Mustapha K, Babba H. Screening of antileishmanial
activity from marine sponge extracts collected off the Tunisian coast. Parasitol Res. 2010;106:1281–6.
 Anti-Viral

Anti-herpes simplex virus-1 (HSV)

activity found in high molecular

weight exo-polysaccharides

extracted from the Celtodoryx

girardae (French marine sponge)

Rashid ZM, Lahaye E, Defer D, Douzenel P, Perrin B, Bourgougnon N, et al. Isolation of a sulphated
polysaccharide from a recently discovered sponge species (Celtodoryx girardae) and determination of its
anti-herpetic activity. Int J Biol Macromol. 2009;44:286–93.
 Analgesics
• Ziconotide was originally
extracted from marine snail
Conus magus
• One of the most potent
analgesics
• Acts by blocking N-type of
calcium channels on the primary
nociceptive nerves of the spinal
cord
Skov MJ, Beck JC, de Kater AW, Shopp GM. Nonclinical safety of ziconotide: An intrathecal analgesic of a new
pharmaceutical class. Int J Toxicol. 2007;26:411–21.
 Anti-malarial
• Extracts for Acanthella sp. that is

Japanese sponge contain isonitrile

molecules

• These molecules belong to

kalihinane diterpenoids class which

act as anti-malarials
Miyaoka H, Shimomura M, Kimura H, Yamada Y, Kim HS, Yusuke W. Antimalarial activity of kalihinol A and new
relative diterpenoids from the Okinawan sponge, Acanthella sp. Tetrahedron. 1998;54:13467–74
 Anti-cancer
• Bryostatin- Derived from Bugula neritina

• Contains Sorbicillin derived alkaloids:

Sorbicillactone A and its 2’,3’ dihydro
analogue Sorbicillactone B
• Has shown activity against leukaemia
without visible cytotoxicity
• Sorbicillactone B is derived from
Penicillium chrysogenum which has been
isolated from sponge Ircinia fasciculata
Davies-Coleman M, Veale C. Recent Advances in Drug Discovery from South African Marine
Invertebrates. Marine Drugs. 2015;13(10):6366-6383.
 Anti-cancer
• Keyhole Limpet Hemocyanin is a copper containing
extracellular respiratory protein present in Megathura
crenulata, a marine Gastropod species
• KLH has remarkable immunostimulatory properties in
experimental animals and human, used in experimental
immunology and also clinically as an immunotherapeutic agent
• Mainly used for treating bladder carcinoma

Harris JR, Markl J. Keyhole limpet hemocyanin (KLH): A biomedical review. Micron. 1999;30:597–623.

 Anti-cancer
• Success of KLH is attributed to presence
of the disaccharide epitope Gal (β1-3),
Ga1NAc.

• Epitope of KLH is believed to be cross-

reactive with an equivalent epitope on
the urinary bladder tumour cell surface. 

• cumulative cellular and humoral

immunological responses to KLH lead to
reduction in tumour
 US FDA Approved Drugs

1. Ziconotide

2. Vidarabine

3. Cytarabine

4. Brentuximab Vedotin

5. Eribulin Mesylate

6. Trabectedin
 Ziconotide (Prialt)
• First drug of marine origin to get US
FDA approval in 2004
• One of the most potent analgesic
known to date
• Non-opioid, non- NSAID, non-local
anaesthetic used to treat chronic pain
• Ziconotide is a 25 amino acid, polybasic
peptide containing three disulfide
bridges
[Internet]. Accessdata.fda.gov. 2018 [cited 8 June 2018]. Available from:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021060s003lbl.pdf
 Ziconotide (Prialt)
• Contains synthetic form of the cone snail peptide ω- conotoxin

• Blocks N-type of Calcium channels in the spinal cord

• Must be administered intra-thecally

• Adverse effects: Dizziness, nausea, confusion, new onset or

worsening depression
 Vidarabine
• Vidarabine is a synthetic purine
nucleoside isolated from Caribbean
sponge T. crypta & developed from
Spongouridine
• Was used to treat recurrent
epithelial keratitis caused HSV type
1 & 2 with acute kerato-
conjunctivitis
• Currently it is NOT marketed
Mayer AM, Glaser KB, Cuevas C, Jacobs RS, Kem W, Little RD, et al. The odyssey of marine
pharmaceuticals: A current pipeline perspective. Trends Pharmacol Sci. 2010;31:255–65.
 Cytarabine
• Synthetic pyrimidine nucleoside
derived from spongothymidine &
isolated from Caribbean sponge
Tethya crypta
• Indicated for use in Acute Myeloid
Leukaemia (AML), Acute
Lymphoblastic Leukaemia (ALL)
and lymphomatous meningitis
• Also possesses antiviral activity
[Internet]. Accessdata.fda.gov. 2018 [cited 8 June 2018]. Available from:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021041s031lbl.pdf
 Cytarabine
• Acts by rapidly converting into cytosine arabinoside

triphosphate which damages DNA when cell cycle is in S phase

• Also act by inhibiting DNA & RNA polymerases

• Adverse Effects: Headache, Arachnoiditis, abnormal gait,

confusion, memory impairment and hypothesias

 Brentuximab Vedotin (Adcetris)
• Approved by US FDA on 20th March
2018 for treatment of stage III & stage
IV classical Hodgkin's lymphoma
• It is an Antibody-Drug Conjugate (ADC)
and it attacks CD 30 receptor of
malignant cells
• Adverse Effects: Neutropenia, anaemia,
neuropathy, nausea, fatigue,
constipation, diarrhoea and pyrexia
[Internet]. Accessdata.fda.gov. 2018 [cited 8 June 2018]. Available from:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125388_S056S078lbl.pdf
 Erbulin mesylate ( Halaven)
• Approved by US FDA in August 2016
for treatment of liposarcoma that
cannot be treated surgically
• Synthetic molecule based on
Halichondrin B present in marine
sponge Halichondria okadai
• Also used in treatment of patients
having metastatic breast cancer
[Internet]. Accessdata.fda.gov. 2018 [cited 8 June 2018]. Available from:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/201532lbl.pdf
 Erbulin mesylate (Halaven)
• Acts as micro-tubule inhibitor and thus shows anti-mitotic

activity

• Prior therapy with anthracycline or taxanes before initiating

this drug

• Adverse Effects: Neutropenia, anaemia, fatigue, alopecia,

nausea and constipation

 Trabectedin (Yondelis)
• Marine natural product extracted from
tunicate Ecteinasadia turbinata,
inhibitant of Mediterranean & Caribbean
sea
• US FDA has granted orphan drug status
for treatment of patients with advanced
soft tissue sarcoma and ovarian cancer
• Induces broad inhibition of activated
transcription
[Internet]. Accessdata.fda.gov. 2018 [cited 8 June 2018]. Available from:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207953s000lbl.pdf
Drugs In Pipeline
 Drugs in Pipeline
• Preclinical pharmacology of 262 marine substances, various
stages of study spreading over 35 countries including the US &
India
• Promising antibacterial, antifungal, antiprotozoal, antitubercular,
and antiviral activities reported for 102 natural marine
compounds
• Mayer et al: 68 promising molecules extracted from marine
sources were found to interact with an array of molecular targets
and receptors
 Marine Pharmacology in India
• Indian scenario is still in nascent stage
waiting to be explored

• Handful of institutions in India working

for exploration of life saving drugs from
marine sources are:
1. National Institute of Oceanology, Goa
2. Central Drug Research Institute
(CDRI), Lucknow
3. Central Institute of Fisheries
Education, Mumbai
Thakur NL, Thakur AN, Muller WEG. Marine natural products in drug discovery. Natural Product
Radiance. 2005;4:471–7.
 Limiting Factors
• Supply: Sustainable supply to ensure a
sequential pathway of preclinical-
clinical investigations
• Formulation: Identification of a
feasible clinical formulation
• Analytical method: Structural
complexity of drugs makes it difficult
to find comprehensive analytical
methods
 Measures to maintain supply
• Mariculture: Farming the marine
organism in its natural
environment
• Aquaculture: Culture of organisms
under artificial conditions
• Hemi synthesis: Use of natural
parent compound as starting point
followed by industrially effective
synthetic process
 Summary
• Marine environment has become a promising source of natural

products, molecules, and drugs of therapeutic use

• Marine active products can be divided into various classes out of

which anticancer, anti-inflammatory, analgesics, and antivirals

have shown excellent results

• Currently six drugs of marine origin have been approved by US

FDA and many drugs are currently in the pipeline

 Summary
• Marine pharmacology in India is still in its nascent stage with

lot of scope for further development

• Major limiting factor is lack of sustainable supply of active

principle

• Mariculture, aquaculture and hemi synthesis of drugs are few

solution to maintain sustained supply

THANK YOU!