MArine anticancer agents

1. Anticancer drugs from Marine Sources

2. Why marine sources?
2

3. Competition for survival and
environmental pressure
Biodiversity
Defence
Attack
Signalling
Chemical Diversity
Potential new drugs
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Marine flora Chemical Biological activity
Microbial flora
Microcystis aeruginosa
MicroviridinToxin BE-4,
Siatoxin
Antibiotic, anticancer
Streptomyces peucetius Daunorubicin
Anticancer activities on acute myeloid leukemia and
acute lymphocytic leukemia
Algal flora
Cyanobacteria Nostoc
linckia and Nostoc
spongiaeforme var.
tenue
Borophycin
Cytotoxicity against human epidermoid carcinoma
(LoVo)and human colorectal adenocarcinomaactivity
Cyanobacteria Apratoxins Inhibit a variety of cancer cell lines
Nostoc linckia Cyptophycin 1
Cytotoxicity against human tumor cell lines and human solid
tumors
Nostoc spongiaeforme Cryptophycin 8
Greater therapeutic efficiency and lower toxicity than
cryptophycin 14 in vivo
Stylopodium sp. Stypoldione Cytotoxic
Table : Some of the marine floral derivatives and their anticancer activities.

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Chondria sp. Condriamide A Cytotoxicity
Caulerpa sp. Caulerpenyne Cytotoxicity, anticancer, antitumour, and antiproliferating activity
Cystophora sp. Meroterpenes and Usneoidone Antitumour
Symploca sp. Largazole Antiproliferative activity
Lyngbya boulloni apratoxin A Cytotoxicity to adenocarcinoma
Leptolyngbya sp. coibamide A Cytotoxicity against NCIH460 lung and mouse neuro2a cells
Stigonema sp. Scytonemin Antiproliferative and anti-inflammatory activities
Acanthophora spicifera Crude
Tumoricidal activity on Ehrlich’s ascites carcinoma cells
developed in mice
Acanthophora spicifera Crude Antioxidants and inhibiting cancer cell proliferation
Palmaria palmata
Phloroglucinol and its polymers, namely,
eckol (a trimer), phlorofucofuroeckol A (a
pentamer), dieckol, and 8,8-bieckol
(hexamers)
Antioxidant activity of the phlorotannins
Eisenia bicyclis
Phloroglucinol and its polymers, namely
eckol (a trimer), phlorofucofuroeckol A (a
pentamer), dieckol, and 8,8-bieckol
(hexamers)
Antioxidant activity of the phlorotannins
Sargassum thunbergii Crude
Antitumour activity, inhibition of tumour metastasis in rat
mammary adeno carcinoma cell (13762 MAT)
Ascophyllum nodosum Fucoidan
Antiproliferative antitumour, anticancer, antimetastatic, and
fibrinolytic
Mangroves and other coastal plants
Ceriops decandra Lignins Antioxidant
Ceriops decandra Mangrove tea Anticancer
Acanthus ilicifolius Ribose derivatives of benzoxazoline Anticancer
Calophyllum inophyllum
Xanthone, biflavonoids, benzophenones,
neoflavanoids, and coumarin derivatives
Anticancer, antitumour, and lipid peroxidation

6. Table: Clinical status of marine derived antitumor agents, their chemical class and mode of action.
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Compound Name Chemical Class Organism Mode of action Company Status
Cytarabine, Ara-C Nucleoside Sponge DNA Polymerase Inhibitor Bedford, Enzon Approved
Trabectedin (ET-743) Alkaloid Tunicate Cell cycle arrest PharmaMar Approved
Eribulin Mesylate
(E7389)
Macrolide Sponge Microtubule interfering agent Eisai Inc. Phase III
Soblidotin (TZT 1027) Peptide Bacterium
Microtubule interfering and
vascular disrupting agent
Aska
Pharmaceuticals
Phase III
Squalamine lactate Aminosteroid Shark
Calcium binding protein
antagonist
Genaera Phase II
Cemadotin Peptide Sea slug Microtubule interfering agent Knoll Phase II
Plinabulin (NPI-2358) Diketopiperazine Fungus Vascular disrupting agent
Nereus
Pharmaceuticals
Phase II
Plitidepsin Depsipeptide Tunicate Apoptosis inducer PharmaMar Phase II

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Elisidepsin Depsipeptide Mollusc - PharmaMar Phase II
Zalypsis Alkaloid Nudibranch Cell cycle arrest PharmaMar Phase II
Tasidotin, Synthadotin
(ILX-651)
Peptide Bacterium
Microtubule interfering
agent
Genzyme
Corporation
Phase II
Discodermolide Polyketide Sponge
Microtubule interfering
agent
Novartis Phase I
HT1286 Dipeptide Sponge
Microtubule interfering
agent
Wyeth Phase I
LAF389
Amino acid
derivative
Sponge
Methionine aminopeptidase
inhibitor
Novartis Phase I
Kahalalide F Cyclic depsipeptide Sea slug/alga Lysosomotropic PharmaMar Phase I
KRN7000
-
galactosylceramide
Sponge Immunostimulatory Kirin Phase I
Bryostatin 1 Polyketide Bacterium/ Bryozoa PKC isozyme inhibitor
National Cancer
Institute
Phase I

8. 9 The Caribbean sea-squirt Ecteinascidia
ecteinascidins

9. Ecteinascidin-743 (ET-743 /Trabectedine)
Yondelis™ by PharmaMar/Johnson & Johnson/OrthoBiotech)
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 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 turbinate
 the yield for ET-743 from the tunicate is very low (~10 parts per million)

10. Structure of Ecteinascidin
11 Rinehart and Wright et
al,1990
•Three fused tetrahydro-isoquinoline rings
•The connection of the third tetrahydroisoquinoline ring to the base structure by a thioether
bridge completes a 10-membered lactone - a distinctive structural feature of ecteinascidins
•8 rings, 7 chiral centers

11. Cytotoxic Activity
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 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

12. Synthesis
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 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

13. Mechanism of Action
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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

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• 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 compound becomes
'activated' into its reactive oxazolidine form.

15. Pharmacokinetic data
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 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

16. Possible side effects :
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 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…

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• One of the most effective agents in AML
– incorporated into all standard induction
regimens in combination with an
anthracycline (7+3)
– component of consolidation and maintenance
regimens after remission is attained
• Active against other hematologic malignancies
– NHL, ALL, and CML
– Regimens include HyperCVAD p2, ESHAP,
DHAP
• Little activity against solid tumors
– lack of metabolic activation in solid tumors
– selective action against rapidly dividing cells
• Clinical efficacy depends on dose and schedule
– short biologic half-life
Ara-C, Arabinosylcytosine
CYTARABINE Injection by Pfizer

18. Structure of ARA-C
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19. Mechanism of Action :
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PHARMACOKINETICS
 Ara-c degraded to ara-u by cytidine deaminase and ara-cmp to
inactive ara-ump by dcmp deaminase
 CSF levels are about 40 – 50% of the plasma level (lack of cytidine
deaminase activity in CSF)
 Distributes widely into total body water, also distributes to tear fluid
and crosses into CNS
SIDE EFFECTS
• Cerebellar toxicity when given in high doses, which may lead to ataxia.
• Granulocytopenia and thrombocytopenia, which may lead to hemorrhage.
• Other Toxicity: leukopenia, thrombocytopenia, anemia,
stomatitis, conjunctivitis, pneumonitis, fever, and dermatitis, palmar-
plantar erythrodysesthesia.

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Thank You!