1. Ramzi A. Mothana, PhDPHG220, Marine Natural Products1 Marine Natural Products

2. Ramzi A. Mothana, PhDPHG220, Marine Natural Products2 Importance of marine environment More than 70 % of the planet’s surface is covered by oceans. The great biodiversity of marine environment. More than 300 000 species of plants and animals are described. Great number of marine organism have no terrestrial counterparts.

3. Ramzi A. Mothana, PhDPHG220, Marine Natural Products3 The very special living condition for marine organisms led them to adapt different physiological and behavioural characters which consequently resulted in novel biologically active molecules. Sea organisms are mostly unexplored reservoirs of new drugs. A small number of marine plants, animals, and microbes have already yielded more than 12000 novel chemicals. Hundreds of new compounds still being discovered every year

4. Ramzi A. Mothana, PhDPHG220, Marine Natural Products4 Phases of work on marine chemistry In the 1950’s researchers were interested in studying the marine spines and shells of sea urchins with beautiful colors. In the 1970’s interest of researchers was attracted to the halogenated metabolites from red algae. From the 1980’s till now the marine chemistry was directed by the currently used sophisticated and smart biological assays. Interest switched from marine algae to marine invertebrates.

5. Ramzi A. Mothana, PhDPHG220, Marine Natural Products5 Problems of marine research 1- The lack of trained personal. 2- Diving hazards. 3- The marine trips are effort, time and money consuming. 4- The time consuming experiments. 5- The scarcity of the starting organism to carry out the complete study. 6- Recollection problems of the same organisms in the dynamic environment.

6. Ramzi A. Mothana, PhDPHG220, Marine Natural Products6 7- Difficulties in culturing of marine organisms in the lab. 8- Most of the marine secondary metabolites are polar compounds, so additional difficulties with extraction, fractionation and separation are faced. 9- The marine organisms are usually associated with parasitic commensal or symbiotic flora. 10- The lack of folk medicine information or ethnobotanical documentation.

7. Ramzi A. Mothana, PhDPHG220, Marine Natural Products7 The marine biosphere Marine organisms are classified into the following phyla: Monera Protista Metazoa Higher plants

8. Ramzi A. Mothana, PhDPHG220, Marine Natural Products8 Monera Monerans are one-celled organisms that have no nucleus or organelles. Monerans are individual cells that survive on their own. They do not work together in groups. However, they can be found in pairs, clumps, or in chains. The kingdom of Monera is divided into two types or organisms, bacteria and cyanobacteria.

9. Ramzi A. Mothana, PhDPHG220, Marine Natural Products9 They make their own food through the process of photosynthesis. These cells are found in oceans, lakes, ponds, swimming pools, and moist soil. They are an important food source for many of the animals in the water. They can be found alone, in colonies, or long thread like chains. Cyanobacteria (blue-green algae )

10. Ramzi A. Mothana, PhDPHG220, Marine Natural Products10 Protista a diverse group of eukaryotic microorganisms. unicellular, or multicellular without specialized tissues. They include marine fungi and algae. 1- Marine fungi live saprophytic on algae, plants or animals. parasites on shells, crabs, sponges, in the GIT of fishes. Or symbiotic as in lichens. Source of antibacterial, antifungal, cytotoxic and anti- inflammatory agents. produce several secondary metabolites e.g. alkaloids, terpenoids and polyketides.

11. Ramzi A. Mothana, PhDPHG220, Marine Natural Products11 2- Algae are a large and diverse group of simple, typically autotrophic organisms, ranging from unicellular to multicellular forms. They are photosynthetic and simple. There are nearly 30,000 algae species. They could be divided into the following groups: 1- Red algae (Rhodophyta) 2- Brown algae (Phaeophyta) 3- Green algae (Chlorophyta) 4- Golden brown algae 5- Yellow algae and diatoms (Chrysophyta) 6- Euglenophyta 7- Blue green algae 8- Dinoflagellates (Pyrrophyta)

12. Ramzi A. Mothana, PhDPHG220, Marine Natural Products12 Chlorophyta (green algae) About 8000 species. Mostly live in fresh water. Chlorophyll a and c.

13. Ramzi A. Mothana, PhDPHG220, Marine Natural Products13 Rhodophyta (red algae) About 5000 – 6000 species. 95% are marine. Chlorophyll a, phycoerythrin.

14. Ramzi A. Mothana, PhDPHG220, Marine Natural Products14 Phaeophyta (brown algae) About 1500-2000 species. 99% are marine. Chlorophyll a, c and phycoerythrin.

15. Ramzi A. Mothana, PhDPHG220, Marine Natural Products15 Marine animals (Metazoa) Marine vertebrates and invertebrates were subjected to chemical study. These studies covered representative phyla: Porifera Cnidaria Mollusca Echinodermata Annelida Chordata

16. Ramzi A. Mothana, PhDPHG220, Marine Natural Products16 Porifera (Sponges الأسفنج) Over 9000 known species and as many species not yet described. Aquatic sessile filter feeders. Simplest animals, multicellular organisms with specialized cells found in a various forms, no organs. 50% of the natural products reported from marine invertebrates. About 2600 metabolites were isolated.

17. Ramzi A. Mothana, PhDPHG220, Marine Natural Products17 Cnidaria This phylum include: soft and hard corals, gorgonians, sea pens, jellyfish, sea wasps and sea anemones. Simple structure: a sac-like body with single opening that functions as both mouth and anus, one or more circles of tentacles surrounding the mouth, an internal space called the coelenteron, which serves for digestion and circulation. Cnidarians have two body forms: 1- Polyp - stationary, vase-shaped e.g. hydra, coral, sea anemone 2- Medusa - swimming, cup-shaped e.g. jellyfish, portuguese man of war. More than 10000 described species. Only 12% were chemically investigated. About 1500 metabolites were isolated.

18. Ramzi A. Mothana, PhDPHG220, Marine Natural Products18 Sea pens Sea anemones شقائق النعمان Jellyfishقنديل البحر

19. Ramzi A. Mothana, PhDPHG220, Marine Natural Products19 Portuguese man of war Corals المرجان Jellyfish

20. Ramzi A. Mothana, PhDPHG220, Marine Natural Products20 Mollusca الرخويات This phylum contains a highly diverse group of animals including 50000 species and 60000 fossil molluscs. vary greatly in physical appearance, size, and feeding habits. include snails الحلزون, tusk shells, shellfish المحار, octopus الإخطبوط, squids حبار, mussels بلح البحر

21. Ramzi A. Mothana, PhDPHG220, Marine Natural Products21 Squids حبار Octopus Mussels بلح البحر

22. Ramzi A. Mothana, PhDPHG220, Marine Natural Products22 Chordata حبليات This phylum includes tunicates and vertebrates. The most distinctive morphological features of chordates are the notochord, nerve cord, and visceral clefts and arches. About 1500 species of tunicates. Tunicates

23. Ramzi A. Mothana, PhDPHG220, Marine Natural Products23 Echinodermata قنفذيات او شوكيات With 7000 extant and 13000 extinct species. They are deuterostomes, a deuterostom being an animal in which the anus is formed from the blastopore during development and the mouth arises as a secondary invagination.

24. Ramzi A. Mothana, PhDPHG220, Marine Natural Products24 Marine secondary metabolites

25. Ramzi A. Mothana, PhDPHG220, Marine Natural Products25 Antitumor and Cytotoxic Agents 1- Didemnins Group of cyclic depsipeptides isolated from Trididemnum species (Tunicates). This tunicate present as a grey-green coating on rocks or coral at depths of 120 feet. It is a source of several didemnins like A, B, C, D, E, G, X and Y. These compounds are cytotoxic, antiviral and immunosuppressive. The most potent one is didemnin B, which is in phase II clinical trial as anticancer agent. It causes inhibiting protein synthesis.

26. Ramzi A. Mothana, PhDPHG220, Marine Natural Products26 Trididemnum cereum Didemnin B

27. Ramzi A. Mothana, PhDPHG220, Marine Natural Products27 2- Dolastatins Group of cyclic and linear peptides and depsipeptides. Isolated from the sea hare Dollabella sp. (1 mg per 100 kg). Dolastatine 10 is the most active one of this series. The dolastatins are mitotic inhibitors. They interfere with tubulin formation and thereby disrupt cell division by mitosis. Phase II clinical trials of dolastatin 10 in patients with several types of tumors have been completed. Later dolastatins 11 and 12 were isolated from cyanobacterium.

28. Ramzi A. Mothana, PhDPHG220, Marine Natural Products28 Dolabella sp. Dolastatine 10

29. Ramzi A. Mothana, PhDPHG220, Marine Natural Products29 3- Bryostatins Group of macrolide lactones isolated primarily from the bryozoan Bugula neritina, also from sponges and tunicates. It is believed to be produced by symbiont bacteria to protect the bryozoan larva from predation or infection. Bryostatin-1 is the most active one (a potent activator of protein kinase C). In vitro trials have shown bryostatins to act synergistically with other anti-cancer drugs and to modulate protein kinase C (PKC) activity, with a potent antileukemic effect and action against lung and prostate tumor cells.

30. Ramzi A. Mothana, PhDPHG220, Marine Natural Products30 Bryostatin has appeared very promising enhancing memory in animal models. It is now being investigated in human testing, possibly for treatment of Alzheimer's disease. Bryostatin is thought to potentiate memory by activating PKC. Bugula neritina Bryostatin-1

31. Ramzi A. Mothana, PhDPHG220, Marine Natural Products31 4- Alkaloids A- Ecteinascidins They are complicated alkaloids isolated from the tunicate Ecteinascidia turbinata. Ecteinascidin 743 is in clinical trials as anticancer agent. B- Niphatesine D Antineoplastic alkaloid which was isolated from Niphates sp. (sponge). C- Clavepictine A and B isolated from the tunicate Clavelina picta. D- Polycarpine Dimeric disulphide alkaloid isolated from Polycarpa clavata.

32. Ramzi A. Mothana, PhDPHG220, Marine Natural Products32 Ecteinascidin 743 Ecteinascidia turbinata

33. Ramzi A. Mothana, PhDPHG220, Marine Natural Products33 Niphates sp. (sponge).

34. Ramzi A. Mothana, PhDPHG220, Marine Natural Products34 Clavelina picta Polycarpa sp. (Tunicate)

35. Ramzi A. Mothana, PhDPHG220, Marine Natural Products35 5- Terpenoids A- Suberosenone Sesquiterpene isolated from the coelenterate Subergorgia suberosa. B- Cembranoids Isolated from from Sinularia gibberosa e.g. 11, 12- epoxycembratrien-15-ol. C- Sarcoglane a diterpene isolated from Sarcophyton glaucum

36. Ramzi A. Mothana, PhDPHG220, Marine Natural Products36 Subergorgia suberosa. Sinularia gibberosa

37. Ramzi A. Mothana, PhDPHG220, Marine Natural Products37 Antiviral active compounds 1- Didemnins See antitumor and cytotoxic compounds. 2- Avarol and avarone S esquiterpenes attached to quinone or hydroquinone unit isolated from a sponge, Disidea avara. These compounds inhibit the human immunodeficiency virus, (inhibit viral reverse transcriptase activity). have high therapeutic indices and the ability to cross the blood–brain barrier.

38. Ramzi A. Mothana, PhDPHG220, Marine Natural Products38 AvaroneAvarol Disidea avara

39. Ramzi A. Mothana, PhDPHG220, Marine Natural Products39 3- Cyanovirin-N (CV-N) is a protein produced by the cyanobacterium that Nostoc ellipsosporum. It displays virucidal activity against several viruses, including HIV. It Prevents virus-to-cell fusion, viral entry and infection of cells. It is of particular interest because of its relative safety (10,000 times more toxic to HIV than it is to cells(.

40. Ramzi A. Mothana, PhDPHG220, Marine Natural Products40 3- Patellazole B isolated from the tunicate, Lissoclinum patella has very potent in vitro activity against herpes simplex viruses. 4- Eudistomins Group of alkaloids isolated from a tunicate Eudistoma olivaceum. Have a β-carboline moity. The most active are eudistomin C,E, K and L 5- Ara-A a semi-synthetic substance based on the arabinosyl nucleosides, isolated from the sponge Tethya crypta. It is arabinosyl adenine (the only compound reported to have significant therapeutic activity). Ara-c is used as antileukemic. Both act by inhibition of DNA synthesis.

41. Ramzi A. Mothana, PhDPHG220, Marine Natural Products41 Eudistoma olivaceum

42. Ramzi A. Mothana, PhDPHG220, Marine Natural Products42 Tethya sp. Ara-A Tethya crypta

43. Ramzi A. Mothana, PhDPHG220, Marine Natural Products43 6- Hennoxazoles Hennoxazoles A-D were isolated from sponge. Characterized by the presence of 2 oxazole units. Hennoxazole A showed an analgesic and a strong anti-HIV-1 activity. 7- Solenolides and Briantheins They are briarein diterpenoids, containing lacton ring. Isolated from gorgonian organisms. The most active is solenolide A. Briarein diterpenoids have weaker antiviral effect comparing to Solenolides. Brianthein Y has also an insecticidal effect.

44. Ramzi A. Mothana, PhDPHG220, Marine Natural Products44

45. Ramzi A. Mothana, PhDPHG220, Marine Natural Products45 Antibacterial active compounds 1- Squalamine is the first aminosterol isolated from the dogfish shark Squalus acanthias (squalidae). It has potent antimicrobial activity against Staphylococcus aureus and antitumour properties. in clinical trials for the treatment of advanced non-small-cell lung cancer. 2- Cribrostatins isolated from a blue sponge Cribrochalina sp. and showed potent antineoplastic and antimicrobial activities. Cribrostatin 3 has potent inhibitory activity against penicillin- resistant Neisseria gonorrheae

46. Ramzi A. Mothana, PhDPHG220, Marine Natural Products46 Dogfish shark

47. Ramzi A. Mothana, PhDPHG220, Marine Natural Products47 Cribrostatin 6 Cribrochalina sp.

48. Ramzi A. Mothana, PhDPHG220, Marine Natural Products48 3- Bromosphaerone potent antibacterial diterpene, isolated from the red alga Sphaerococcus coronopifolius. It shows antibacterial activity against S. aureus. 4- Pestalone Obtained as a result of a fermentation of marine fungus (the genus Pestalotia) with marine bacterium. Pestalone has potent antibiotic activity against methicillin-resistant S. aureus and vancomycin-resistant Enterococcus faecium. 5- Jorumycin a dimeric isoquinoline alkaloid that was isolated from the mantle and mucus of the Pacific nudibranch (Mollusca) Jorunna funebris. It inhibits the growth of various Gram- positive bacteria.

49. Ramzi A. Mothana, PhDPHG220, Marine Natural Products49 Jorumycin

50. Ramzi A. Mothana, PhDPHG220, Marine Natural Products50 Antifungal active compounds 1- Jasplakinolide (Jaspamide) a 19-membered macrocyclic cyclodepsipeptide isolated from a sponge (a Jaspis sp.) selective in-vitro antimicrobial activity against Candida albicans. 2- Gambieric acids are extremely potent antifungal metabolites isolated from a strain of the epiphytic marine dinoflagellate Gambierdiscus toxicus. are the first antifungal representatives of the brevetoxin-type (fused polyether rings) structures, consisting of nine contiguous ether rings and one isolated tetrahydrofuran.

51. Ramzi A. Mothana, PhDPHG220, Marine Natural Products51 Gambieric acid A inhibits the growth of Aspergillus niger at a concentration of 10 ng/disk. The potency of gambieric acids exceeds that of amphotericin B by 2000-fold. Most antifungal compounds from marine origin are cytotoxic. Consequently, they have not generally been considered promising antifungal agents for clinical applications

52. Ramzi A. Mothana, PhDPHG220, Marine Natural Products52 brevetoxin-type

53. Ramzi A. Mothana, PhDPHG220, Marine Natural Products53 3- Hamacanthin A and Hamacanthin B Indole alkaloids isolated from Hamacantha sp. They inhibit the growth of opportunistic fungal pathogens Hamacanthin A Hamacanthin B

54. Ramzi A. Mothana, PhDPHG220, Marine Natural Products54 Antiprotozoal active compounds 1- Cyclic peroxides Isolated from sponges (Plakortis sp.) are well known Two isolated peroxides are active against Leishmania mexicana. The most active cyclic peroxide causes lysis of the cell membrane after 24h. however, less effective than ketoconazole. 2- Manzamine A an alkaloid displays 70% inhibition of the T. gondii parasite, at 0·054 g/mL concentration, without cell toxic effects.

55. Ramzi A. Mothana, PhDPHG220, Marine Natural Products55 Anti-inflammatory Agents 1- Manoalide Isolated from Luffariella variabilis Irreversibly inhibits phospholipase A2 2- Dysidine Isolated from Dysidea sp. Exerts higher potency and selectivity toward phospholipase A2 than manoalide. 3- Cordiachromen A Isolated from Aplidium multiplicatum Strong anti-inflammatory effect similar to that of indomethacin It inhibits prostacyclin synthesis (inhibition of cyclooxygenase pathway.

56. Ramzi A. Mothana, PhDPHG220, Marine Natural Products56 Manoalide Dysidine Cordiachromen A

57. Ramzi A. Mothana, PhDPHG220, Marine Natural Products57 4- Pseudopterosins Pseudopterosins isolated from Pseudopterogorgia bipinnata. They inhibit PGs and LTs biosynthesis It exhibited potent anti- inflammatory and analgesic activities Pseudopterosin A Pseudopterosin C

58. Ramzi A. Mothana, PhDPHG220, Marine Natural Products58 Pseudopterogorgia sp.