Marine organisms produce complex chemicals as defenses against predators or competitors in the ocean environment. These chemicals show potential for developing new drugs, with some already in medical use. Ziconotide from cone snails is a potent non-opioid painkiller administered intrathecally. Ecteinascidin-743 from a Caribbean tunicate was the first marine-derived anticancer drug approved. It alkylates DNA and induces apoptosis. Both drugs show activity against cancers and have complex mechanisms of action involving ion channels or DNA damage, respectively. Marine natural products continue to offer possibilities for new pharmaceuticals.

1. DRUGS FROM MARINE
SOURCES
PRINCE
1111038
Principles of drug
design

2. Why marine sources?
2

3. Competition for survival and
environmental pressure
Biodiversity
Defence
Attack
Signalling
Chemical Diversity
Potential new drugs
4

4. Marine natural Products
 Many natural products from these
organisms act as chemical weapons and
are highly potent inhibitors of
physiological processes in prey,
predator or competitor
 Several show pharmacological activities
and are effective against cancer, AIDS,
arthritis
 Highly potent
6

5. • α- and αA-conotoxins -competitively inhibited
Nicotinic acetylcholine receptors (nAChR)
•ψ-conotoxins noncompetitive
inhibition of this family of receptors.
•σ-conotoxins - antagonize the
related
5-HT3 serotonin receptor
•ω-conotoxins - calcium-channe
blockers
Harfner et al,2003
•κ-conotoxins - potassium-chan
blockers•μ-, as well as μO-conotoxins
sodium channel blockers
And many other conotoxins…
Conus magus (Cone snail)
8

6. Ziconotide
Prialt™, Azur Pharma
 Synthetic equivalent of naturally
occurring ω-conotoxin MVIIA
 It is considered medically necessary for
the management of severe chronic pain
in those individuals for whom intrathecal
(IT) therapy is warranted, and who are
intolerant of or refractory to other
treatment, such as systemic analgesics,
adjunctive therapies or IT morphine.
 It is administered by intrathecal infusion
10

7. Intrathecal infusion
11

8. Biology and chemistry of
Ziconotide
•Amino acid sequence of -MVIIA, illustrating the
characteristic disulphide linkage pattern between
the six cysteine residues. The three disulphide
bridges serve to stabilize the native conformation
of the toxin and cause the peptide to display 4
loops, some of which contain important structural
determinants of N-type calcium channel blocking
activity, eg, tyrosine-13
12

9. Three-dimensional structure of
the synthetic ω-conotoxin MVIIA polypeptide. The
cylinder
represents the amide backbone of ω-conotoxin VIIA
overlayed against an electrostatic potential surface.
13

10. Pharmacology
• 25-amino acid peptide
• Six cysteine residues linked by 3 disulfide
bonds
Pharmacodynamics :
N-type voltage-sensitive calcium
channels (NVSCCs) were subsequently
identified as
its target site. It potently inhibits the
conduction of nerve signals by specifically
blocking the NVSCC. In the complex with
NVSCC, it forms a compact folded structure
with a binding loop between Cys8 and Cys1514

11. 15

12. 16

13.  Direct blockade of N-type channel inhibits the
activity of a subset of neurons, including pain-
sensing primary nociceptors which are controlled
by the former
 50 times more effective than morphine
 N-Ca Channel
(Miljanich 2004)
17

14. Pharmacokinetics
 Bioavailability = 50%
 Rat model : ED50 = 49pM (Morphine ED50 =
2.1nM)
 Half life = 1.3 hour
 Excretion = <1% urine
 Tmax = 5.3 hour
 Oral,Mouse : LD50 = 300 mg/kg
 Oral, rabbit : LD50 = 3200 mg/kg
 Oral, rat : LD50 = 980 mg/kg
Yaksh et al,2012
18

15. Side effects
 Most frequent : Dizziness, nausea, confusional
state and nystagmus (>25%)
 Meningitis, when infused with an external
catheter
Cases of meningitis were not observed when an
internal catheter was surgically implanted.
 Side effects are to be weighed against high level
of pain management, its degree and length and
also lack of dependence and tolerance even after
long treatment when most other drugs do not
work.19

16. 20 The Caribbean sea-squirt Ecteinascidia
ecteinascidins

17. Ecteinascidin-743 (ET-743 /
Trabectedine)
Yondelis™ by PharmaMar/Johnson &
Johnson/OrthoBiotech)
21
 A significant milestone in development of marine
derived drugs.
 First marine-derived anticancer drug to reach the
market – after 40 years of its discovery and 17
years after publication of its structure.
 Extracts of caribbean derived tunicate
Ecteinascidia turbinata• the yield for ET-743 from the tunicate is very low
(~10 parts per million)

18. Structure of Ecteinascidin
22 Rinehart and Wright et
al,1990
•Three fused
tetrahydro-
isoquinoline rings
•The connection of
the third
tetrahydroisoquinolin
e
ring to the base
structure by a
thioether bridge
completes a 10-
membered lactone -
a distinctive
structural
feature ofdetails

19. Cytotoxic Activity
23
 ecteinascidins were found to be cytotoxic
against L1210 leukaemia cells (IC50 value of
0.5 ng per ml)
 strong in vivo antitumour effects in various
mice models bearing P388 lymphoma, B16
melanoma, M5076 ovarian sarcoma, lewis
and lX-1 human lung carcinoma, and MX-1
human mammary carcinoma xenografts

20. Synthesis
24
 the first multistep synthesis of the
compound was completed in 1996
(0.75% yield) (Corey et al, JACS)
 Large scale semi synthesis developed
by PharmaMar that starts with
cynosafracin B which can be produced
by fermentation of Pseudomonas
fluorescens

21. Mechanism of Action :
25
A ring 
C ring 
Fig. Molecular-dynamics model
showing the alkylation of DNA by ET-
743 at N2 of guanine in the minor
groove. The A Ring and C Ring
represent the tetra hydroisoquinoline A
and C rings of ET-743
• Ascribed to covalent
modification of DNA by
guanine-specific alkylation at
the N2 position
• Selective for GC-rich
sequence and forms an
adduct with duplex DNA
which induces a bend in the
DNA helix directed towards
the major groove
Zewail-Foote et al,1999,2001,Takebayashi et al.2001

22. 26
• Protrusion of ring C of ET-743 into minor
groove and interference with DNA
binding factors ET-743 also affects
transition-coupled nucleotide excision
repair and triggers cell death
 Actual mechanism is not yet known but
it is believed to involve the production
of superoxide near the DNA strand
resulting in DNA backbone cleavage
and cell apoptosis.
 There is also some speculation the

23. Success :
28
 Ewing’s sarcoma and soft-tissue sarcomas,
colorectal cancer, pretreated advanced breast
cancer, ovarian cancer, and other sarcomas
 ET-743 has remarkable antitumour activity
against solid tumours, in particular breast cancer
and renal carcinoma, and soft-tissue sarcomas
(particularly osteosarcomas, mesothelioma,
leiomyosarcoma and liposarcoma).
 Cells in the G1 phase of the cell cycle, and of
these softtissue
sarcoma cells in particular, are extremely
sensitive to ET743-induced cell killing

24. Mode of administration :
29
 Intravenous
 through a fine plastic tube that is inserted under
the skin and into a vein near the collarbone
(central line)
 into a fine tube that is inserted into a vein in the
crook of arm (PICC line).
 To help prevent some of the side effects of
trabectedin, you will be given an injection of a
steroid drug 30 minutes before the chemotherapy

25. Pharmacokinetic data
30
 Protien binding : 94 to 98%
 Metabolism : Hepatic (mostly CYP3A4-
mediated)
 Half-life : 180 hours (mean)
 Oral, Mouse : LD50 = 300 mg/kg;
 Oral, rabbit: LD50 = 3200 mg/kg
 Oral, rat:LD50 = 980 mg/kg
 Excretion : Mostly fecal

26. Possible side effects :
31
 Varies from person to person
 Risk of infection as it reduces white blood cell
count
 Bruising and bleeding – it reduces production of
platelates
 Anaemia
 Loss of appetite
 Tiredness…

27. Future of Drugs from marine
sources?
32

28. 33
Thank You!