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DRUGS FROM MARINE
SOURCES
PRINCE
1111038
Principles of drug
design
Why marine sources?
2
Competition for survival and
environmental pressure
Biodiversity
Defence
Attack
Signalling
Chemical Diversity
Potential ne...
Marine natural Products
 Many natural products from these
organisms act as chemical weapons and
are highly potent inhibit...
• α- and αA-conotoxins -competitively inhibited
Nicotinic acetylcholine receptors (nAChR)
•ψ-conotoxins noncompetitive
inh...
Ziconotide
Prialt™, Azur Pharma
 Synthetic equivalent of naturally
occurring ω-conotoxin MVIIA
 It is considered medical...
Intrathecal infusion
11
Biology and chemistry of
Ziconotide
•Amino acid sequence of -MVIIA, illustrating the
characteristic disulphide linkage pat...
Three-dimensional structure of
the synthetic ω-conotoxin MVIIA polypeptide. The
cylinder
represents the amide backbone of ...
Pharmacology
• 25-amino acid peptide
• Six cysteine residues linked by 3 disulfide
bonds
Pharmacodynamics :
N-type voltage...
15
16
 Direct blockade of N-type channel inhibits the
activity of a subset of neurons, including pain-
sensing primary nocicept...
Pharmacokinetics
 Bioavailability = 50%
 Rat model : ED50 = 49pM (Morphine ED50 =
2.1nM)
 Half life = 1.3 hour
 Excret...
Side effects
 Most frequent : Dizziness, nausea, confusional
state and nystagmus (>25%)
 Meningitis, when infused with a...
20 The Caribbean sea-squirt Ecteinascidia
ecteinascidins
Ecteinascidin-743 (ET-743 /
Trabectedine)
Yondelis™ by PharmaMar/Johnson &
Johnson/OrthoBiotech)
21
 A significant milest...
Structure of Ecteinascidin
22 Rinehart and Wright et
al,1990
•Three fused
tetrahydro-
isoquinoline rings
•The connection o...
Cytotoxic Activity
23
 ecteinascidins were found to be cytotoxic
against L1210 leukaemia cells (IC50 value of
0.5 ng per ...
Synthesis
24
 the first multistep synthesis of the
compound was completed in 1996
(0.75% yield) (Corey et al, JACS)
 Lar...
Mechanism of Action :
25
A ring 
C ring 
Fig. Molecular-dynamics model
showing the alkylation of DNA by ET-
743 at N2 of...
26
• Protrusion of ring C of ET-743 into minor
groove and interference with DNA
binding factors ET-743 also affects
transi...
Success :
28
 Ewing’s sarcoma and soft-tissue sarcomas,
colorectal cancer, pretreated advanced breast
cancer, ovarian can...
Mode of administration :
29
 Intravenous
 through a fine plastic tube that is inserted under
the skin and into a vein ne...
Pharmacokinetic data
30
 Protien binding : 94 to 98%
 Metabolism : Hepatic (mostly CYP3A4-
mediated)
 Half-life : 180 h...
Possible side effects :
31
 Varies from person to person
 Risk of infection as it reduces white blood cell
count
 Bruis...
Future of Drugs from marine
sources?
32
33
Thank You!
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Drugs from marine sources

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Drugs from marine sources

  1. 1. DRUGS FROM MARINE SOURCES PRINCE 1111038 Principles of drug design
  2. 2. Why marine sources? 2
  3. 3. Competition for survival and environmental pressure Biodiversity Defence Attack Signalling Chemical Diversity Potential new drugs 4
  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. 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. 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. 7. Intrathecal infusion 11
  8. 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. 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. 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. 11. 15
  12. 12. 16
  13. 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. 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. 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. 16. 20 The Caribbean sea-squirt Ecteinascidia ecteinascidins
  17. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 27. Future of Drugs from marine sources? 32
  28. 28. 33 Thank You!

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