Dr. Harshad Malve

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.

A wide variety of environments

BiodiversityThe 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

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.

Sources of Marine drugsMajority 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

MOLLUSKS

BYROZOA

TUNICATE

SPONGES

Development of Marine pharmacology

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.

Drugs of marine origin:

Ziconotide1st 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

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.

Anti-cancer candidatesEcteinascidin 743

Didemnin B

Dolastatin 10

Halichondrin B

Bryostatin 1

Aplidin (APL)

Kahalalide F (KF)

Ecteinascidin 743A 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

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

Didemnin BCyclodepsipeptide 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

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

Dolastin-10A 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

Halichondrin BThis 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

Bryostatin-1A 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

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.

In phase I studies, tumour responses have been

observed in patients with malignant melanoma,

lymphoma & ovarian carcinoma

Dose-limiting toxicity is myalgias

Cont.

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

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.

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

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

Amphilactams A–S

Geodin A

Anti-helmintics

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

Geodin AGeodin 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

Loloatins A–D

Myticin

Psammaplin A

Anti-bacterials

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

MyticinIsolated 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

Psammaplin AA bromotyrosine derivative from the sponge

Psammaplysilla sp. possessed antibacterial

activity against methicillin-resistant Gram-

positive Staphylococcus aureus

Monoterpenes

Isolated from the marine red alga Plocamium

hamatum

One of them was antitubercular towards

Mycobacterium tuberculosis & Mycobacterium

avium

Anti-tubercular

Bengazole, bengamide

Oceanapiside

Spongistatin I

Tanikolide

Theopederins F–J

Anti-fungals

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.

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.

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

Lamellarin α-20-sulfate

Papuamides A–D

Polycitone A

Glycosaminoglycan

Sulfated β-galactan

Poly-hydroxysteroids

Sansalvamide

Anti-virals

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.

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.

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.

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.

Maitotoxin

A marine toxin causing ciguatera poisoning

Mechanism of action was similar to U46619

- a thromboxane A receptor agonist

Anti-plateletes

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

Anti-inflammatoryAfricanene,

Cacospongiolide B,

Palinurin, Palinurine A and B

Plakotenin

AfricaneneSesquiterpene 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

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 PLA2 in vivo

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 TXB2 and Oxide radicals

ImmunosuppressantsImmunosuppresant activity was reported for

the novel glycolipids simplexides, isolated

from the sponge Plakortis simplex

Showed a 43% inhibitory effect on lymph

node cell proliferation

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)

Measures to maintain supplyControlled & 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

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”