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Marine pharmacology By Dr. Harshad Malve

Marine Pharmacology

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Marine pharmacology By Dr. Harshad Malve

  1. 1. Dr. Harshad Malve
  2. 2. 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.
  3. 3. A wide variety of environments
  4. 4. Biodiversity The 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
  5. 5. 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.
  6. 6. Sources of Marine drugs Majority 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
  7. 7. M O L L U S K S B Y R O Z O A T U N I C A T E S P O N G E S
  8. 8. Development of Marine pharmacology
  9. 9. 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.
  10. 10. Drugs of marine origin:
  11. 11. Ziconotide 1st 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
  12. 12. 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.
  13. 13. Anti-cancer candidates Ecteinascidin 743 Didemnin B Dolastatin 10 Halichondrin B Bryostatin 1 Aplidin (APL) Kahalalide F (KF)
  14. 14. Ecteinascidin 743 A 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
  15. 15. 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
  16. 16. Didemnin B Cyclodepsipeptide 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
  17. 17. 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
  18. 18. Dolastin-10 A 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
  19. 19. Halichondrin B This 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
  20. 20. Bryostatin-1 A 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
  21. 21. 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.
  22. 22. In phase I studies, tumour responses have been observed in patients with malignant melanoma, lymphoma & ovarian carcinoma Dose-limiting toxicity is myalgias Cont.
  23. 23. 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
  24. 24. 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.
  25. 25. 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
  26. 26. 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
  27. 27. Amphilactams A–S Geodin A Anti-helmintics
  28. 28. 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
  29. 29. Geodin A Geodin 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
  30. 30. Loloatins A–D Myticin Psammaplin A Anti-bacterials
  31. 31. 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
  32. 32. Myticin Isolated 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
  33. 33. Psammaplin A A bromotyrosine derivative from the sponge Psammaplysilla sp. possessed antibacterial activity against methicillin-resistant Gram-positive Staphylococcus aureus
  34. 34. Monoterpenes Isolated from the marine red alga Plocamium hamatum One of them was antitubercular towards Mycobacterium tuberculosis & Mycobacterium avium Anti-tubercular
  35. 35.  Bengazole, bengamide  Oceanapiside  Spongistatin I  Tanikolide  Theopederins F–J Anti-fungals
  36. 36. 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.
  37. 37. 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.
  38. 38. 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
  39. 39.  Lamellarin α-20-sulfate  Papuamides A–D  Polycitone A  Glycosaminoglycan  Sulfated β-galactan  Poly-hydroxysteroids  Sansalvamide Anti-virals
  40. 40. 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.
  41. 41. 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.
  42. 42. 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.
  43. 43. 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.
  44. 44. Maitotoxin A marine toxin causing ciguatera poisoning Mechanism of action was similar to U46619 - a thromboxane A receptor agonist Anti-plateletes
  45. 45. 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
  46. 46. Anti-inflammatory Africanene, Cacospongiolide B, Palinurin, Palinurine A and B Plakotenin
  47. 47. Africanene Sesquiterpene 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
  48. 48. 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 PLA2in vivo
  49. 49. 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 TXB2and Oxide radicals
  50. 50. Immunosuppressants Immunosuppresant activity was reported for the novel glycolipids simplexides, isolated from the sponge Plakortis simplex Showed a 43% inhibitory effect on lymph node cell proliferation
  51. 51. 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)
  52. 52. Measures to maintain supply Controlled & 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
  53. 53. 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”

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