PHG 322 Pharmacogonsy II lecture 6 Presented by Assistant Prof. Dr. Ebtesam Alsheddi

1. PHG 322Pharmacogonsy IIlecture 6Presented byAssistant Prof. Dr. EbtesamAlsheddi بسم الله الرحمن الرحيم

2. 6 kingdoms of marine organisms • Bacteriaare single-celled organisms that reproduce by splitting in two. Bacteria live throughout the marine environment. They play a crucial role in ecosystems, breaking down organic material and making nutrients available for the phytoplankton. • Protozoansare single-celled organisms that are generally much larger than bacteria. They may be autotrophic or heterotrophic. In the marine environment, this kingdom is well represented and includes amoebae. • Chromistsrange from very small organisms such as diatoms (a type of phytoplankton) to seaweeds. Most chromistsphotosynthesise but there are some significant differences that have led scientists to classify them separately to plants, for example, they use a different kind of chlorophyll. • Fungirely on breaking down organic material as they are not able to make their own food. There are very few fungi in the marine environment. • Plantsare multi-cellular and autotrophic – they use photosynthesis to produce food using sunlight. Plants are much more widespread on land and in freshwater, and there are only a few types that thrive in the marine environment, for example, eel grass and mangroves. Seaweeds were previously classed as plants before they were reclassified as chromists. • Animalsare typically large and multi-cellular. They are heterotrophic and rely on other organisms for food. Animals in the marine environment include jellyfish, sponges, sea spiders, bryozoans, mussels, sea stars, fish and whales.

3. Nature has played an instrumental role in providing effective therapeutic entities. In fact, terrestrially derived remedies have generally preceded the progress of medicine in the context of the evolution of humankind [1]. Serendipity sequentially linked to a scientifically oriented approach, pioneered by Paracelsus some centuries ago [2] have led to significant discoveries in therapeutic research. In this context, it is important to consider that the major antiinfective, anticancer, analgesics and immunosuppressive compounds are of natural origin. By contrast, the historical relationship between humankind and the sea is usually appreciated as the basis for travelling, trading and as a nutritional source. We live in a planet of oceans. The marine ecosystem covers more than 70% of the earth’s surface but represents 95% of the biosphere [3]. The first living organisms appeared in the sea more than 3500 million years ago [4, 5] and evolutionary development has equipped many marine organisms with the appropriate mechanisms to survive in a hostile milieu in terms of extreme temperatures, changes in salinity and pressure, as well as overcoming the effects of mutation, bacteria and viral pathogens. Marine organisms have developed exquisitely complex biological mechanisms showing cross phylum activity with terrestrial organisms. Self non-self discrimination processes active in colonial tunicates may represent the evolutionary precursor(s) to major histocompatibility complex genes [6] and sea star factor and rabbit lymphokines show cross activity suggesting a phylogenetic link for lymphokines [7]. These biological capabilities are expressed in their ability to synthesize and release potent Mar. Drugs 2004, 2 16 chemical weapons that are active per se, excluding the need for bio-activation; those chemical entities are called secondary metabolites; such a conceptual view might be questioned, in our opinion, since such chemical entities should have played or still be playing relevant biological roles as autocrine cell regulators, regulators of the differentiation process. Another important differential factor deals with biodiversity. All but 2 of the 28 major animal phyla are represented in aquatic environments and some of them are exclusive of the marine ecosystem, such as Ctenophore, Echinodermata, Porifera, Phoronidea, Brachiopoda and Chaetognata [5]. In terms of evolution and biodiversity, the sea appears to be superior to the terrestrial ecosystem ─ one has to consider that the most important biological explosion took place in the marine ecosystem during the Cambrian period 600 million years ago [4] and marine species comprise approximately a half of the total biodiversity, thus offering a vast source from which to discover useful therapeutics. • Sources of marine bioactive compounds include: Marine algae Marine bacteria and fungi Marine invertebrates (= Seaweeds) More recently, it has been recognised that algae fall into several kingdoms. Some, such as the green algae, are plants. Others fall under the kingdom Protista. Prokaryotic algae belong to the kingdom Monera together with the bacteria, but this kingdom should probably be divided into more than one. It has even been suggested that the red algae should have a kingdom of their own. Thus it is easy to see that the 'algae' constitute an artificial grouping of organisms. They aredealt with together because of historial beliefs and for the sake of convenience. Many phycologists, however, still treat the algae as though they were part of the plant kingdom, although recognising that the prokaryotic algae (the blue-green algae) belong with the bacteria. This is mostly so because university structures do not yet reflect the new systems of classification, and courses dealing with algae are usually offered as "Botany" courses.

4. Marine algae • Grow almost exclusively in the shallow waters at the edge of the world's oceans • Seaweeds are plants because they use the sun's energy to produce carbohydrates from carbon dioxide and water. • They are simpler than the land plants mainly because they absorb the nutrients that they require from the surrounding water and have no need for roots or complex conducting tissues • Seaweed draws an extraordinary wealth of mineral elements from the sea which includes sodium, calcium, magnesium, potassium, chlorine, sulfur and phosphorus; the micronutrients include iodine, iron, zinc, copper, selenium, molybdenum, fluoride, manganese, boron, nickel and cobalt • vitamins like carotenes (provitamin A); vitamin C, B12 along with higher proportion of essential fatty acids than land plants.

5. Marine algae (cont.): • Can be classified into three broad groups based on their color: (= Phaeophyceae) (= Rhodophyceae) (= Chlorophyceae) Redseaweeds Green seaweeds Brown seaweeds • Are usually large • Are usually smaller • Also small • Similar in sizeto red seaweeds • Range from: • - Giant size (20 m long) • - Thick, leather- like seaweeds from 2 – 4 m long • - Small species 30 – 60 cm long • Range from: • - Few centimeters to about 1 m in length • Not always red, sometimes purple

6. Red algae Green algae Brown algae Small, microscopic algae which drift about in bodies of water, such as lakes and oceans, are called phytoplankton There is even a unicellular green alga called Prototheca which causes disease in humans, although like this specimen, you have to be very ill already to get it. It produces skin lesions, mainly in patients whose immune systems have been damaged by other serious diseases. The stony corals which construct coral reefs in warm tropical seas are only able to build up these massive and beautiful structures because thet have formed a symbiotic partnership with tiny single-celled algae called zooxanthellae. The zooxanthellae which live in the tissues of the coral, share with it the organic producrts of their photosynthesis, as well as helping the coral with the construction of its limestone skeleton. Even the chloroplast of land plants had its origin as a blue-green alga that lived within the cells of the ancestral organism. Such a special symbiotic relationship, where one organism lives inside the cells of another, is called endosymbiosis

7. Seaweeds are also called “macroalgae”. • This distinguishes them from “microalgae” which are: • - Microscopic in size • - Often unicellular and • - Are best known by the “blue-green”algae that contaminate rivers and streams. Cyanobacteria (blue-green algae) are microorganisms that structurally resemble bacteria (they lack a nucleus and organelles ). However, unlike other bacteria, cyanobacteria contain chlorophyll a and conduct oxygenic photosynthesis • Phycology (from Greek, phykos, "seaweed” and -logia) is the scientific study of algae. • Phycology is a branch of life science and often is regarded as a subdiscipline of botany.

8. Nature has played an instrumental role in providing effective therapeutic entities. In fact, terrestrially derived remedies have generally preceded the progress of medicine in the context of the evolution of humankind [1]. Serendipity sequentially linked to a scientifically oriented approach, pioneered by Paracelsus some centuries ago [2] have led to significant discoveries in therapeutic research. In this context, it is important to consider that the major antiinfective, anticancer, analgesics and immunosuppressive compounds are of natural origin. By contrast, the historical relationship between humankind and the sea is usually appreciated as the basis for travelling, trading and as a nutritional source. We live in a planet of oceans. The marine ecosystem covers more than 70% of the earth’s surface but represents 95% of the biosphere [3]. The first living organisms appeared in the sea more than 3500 million years ago [4, 5] and evolutionary development has equipped many marine organisms with the appropriate mechanisms to survive in a hostile milieu in terms of extreme temperatures, changes in salinity and pressure, as well as overcoming the effects of mutation, bacteria and viral pathogens. Marine organisms have developed exquisitely complex biological mechanisms showing cross phylum activity with terrestrial organisms. Self non-self discrimination processes active in colonial tunicates may represent the evolutionary precursor(s) to major histocompatibility complex genes [6] and sea star factor and rabbit lymphokines show cross activity suggesting a phylogenetic link for lymphokines [7]. These biological capabilities are expressed in their ability to synthesize and release potent Mar. Drugs 2004, 2 16 chemical weapons that are active per se, excluding the need for bio-activation; those chemical entities are called secondary metabolites; such a conceptual view might be questioned, in our opinion, since such chemical entities should have played or still be playing relevant biological roles as autocrine cell regulators, regulators of the differentiation process. Another important differential factor deals with biodiversity. All but 2 of the 28 major animal phyla are represented in aquatic environments and some of them are exclusive of the marine ecosystem, such as Ctenophore, Echinodermata, Porifera, Phoronidea, Brachiopoda and Chaetognata [5]. In terms of evolution and biodiversity, the sea appears to be superior to the terrestrial ecosystem ─ one has to consider that the most important biological explosion took place in the marine ecosystem during the Cambrian period 600 million years ago [4] and marine species comprise approximately a half of the total biodiversity, thus offering a vast source from which to discover useful therapeutics. • Sources of bioactive compounds (cont.): 2) Marine bacteria and fungi: • Of considerable importance as new promising sources of biologically active products. • Up till now, only a small number of microorganisms have been investigated, yet a huge number of active substances have been isolated e.g. some antibiotics. Serratia marcescens Serratia marcescens, a widely distributed non-pathogenic bacterium, had furnished a red coloured antibiotic named prodigiosin.88-96 It exhibited high order of antibiotic and antifungal activities. The high toxicity of prodigiosin precluded its use as a therapeutic agent 6 kingdoms of marine organisms All kingdoms are represented in the marine environment, and most scientists classify marine organisms into one of the following 6 kingdoms. Bacteria are single-celled organisms that reproduce by splitting in two. Bacteria live throughout the marine environment. They play a crucial role in ecosystems, breaking down organic material and making nutrients available for the phytoplankton. Protozoans are single-celled organisms that are generally much larger than bacteria. They may be autotrophic or heterotrophic. In the marine environment, this kingdom is well represented and includes amoebae. Chromists range from very small organisms such as diatoms (a type of phytoplankton) to seaweeds. Most chromists photosynthesise but there are some significant differences that have led scientists to classify them separately to plants, for example, they use a different kind of chlorophyll. Fungi rely on breaking down organic material as they are not able to make their own food. There are very few fungi in the marine environment. Plants are multi-cellular and autotrophic – they use photosynthesis to produce food using sunlight. Plants are much more widespread on land and in freshwater, and there are only a few types that thrive in the marine environment, for example, eel grass and mangroves. Seaweeds were previously classed as plants before they were reclassified as chromists. Animals are typically large and multi-cellular. They are heterotrophic and rely on other organisms for food. Animals in the marine environment include jellyfish, sponges, sea spiders, bryozoans, mussels, sea stars, fish and whales. Substances produced by living organisms found in nature—so-called "natural products"—have played a critical role in the development of drugs for life-threatening conditions. The anticancer agent Taxol was sourced from a plant, penicillin from a fungus, and a number of recent breakthroughs have resulted in the development and approval of anticancer drugs derived from marine sources such as coral and sponges.

9. It was surprising to find that many bioactive compounds, reported from marine invertebrates are produced by their microbial symbionts • Interestingly microorganisms associated with marine invertebrates are proved valuable candidates for drug discovery program

10. Nature has played an instrumental role in providing effective therapeutic entities. In fact, terrestrially derived remedies have generally preceded the progress of medicine in the context of the evolution of humankind [1]. Serendipity sequentially linked to a scientifically oriented approach, pioneered by Paracelsus some centuries ago [2] have led to significant discoveries in therapeutic research. In this context, it is important to consider that the major antiinfective, anticancer, analgesics and immunosuppressive compounds are of natural origin. By contrast, the historical relationship between humankind and the sea is usually appreciated as the basis for travelling, trading and as a nutritional source. We live in a planet of oceans. The marine ecosystem covers more than 70% of the earth’s surface but represents 95% of the biosphere [3]. The first living organisms appeared in the sea more than 3500 million years ago [4, 5] and evolutionary development has equipped many marine organisms with the appropriate mechanisms to survive in a hostile milieu in terms of extreme temperatures, changes in salinity and pressure, as well as overcoming the effects of mutation, bacteria and viral pathogens. Marine organisms have developed exquisitely complex biological mechanisms showing cross phylum activity with terrestrial organisms. Self non-self discrimination processes active in colonial tunicates may represent the evolutionary precursor(s) to major histocompatibility complex genes [6] and sea star factor and rabbit lymphokines show cross activity suggesting a phylogenetic link for lymphokines [7]. These biological capabilities are expressed in their ability to synthesize and release potent Mar. Drugs 2004, 2 16 chemical weapons that are active per se, excluding the need for bio-activation; those chemical entities are called secondary metabolites; such a conceptual view might be questioned, in our opinion, since such chemical entities should have played or still be playing relevant biological roles as autocrine cell regulators, regulators of the differentiation process. Another important differential factor deals with biodiversity. All but 2 of the 28 major animal phyla are represented in aquatic environments and some of them are exclusive of the marine ecosystem, such as Ctenophore, Echinodermata, Porifera, Phoronidea, Brachiopoda and Chaetognata [5]. In terms of evolution and biodiversity, the sea appears to be superior to the terrestrial ecosystem ─ one has to consider that the most important biological explosion took place in the marine ecosystem during the Cambrian period 600 million years ago [4] and marine species comprise approximately a half of the total biodiversity, thus offering a vast source from which to discover useful therapeutics. • Sources of bioactive compounds (cont.): 3) Marine invertebrates: • They are animals that inhabit a marine environment and are, lacking a vertebral column. • In order to protect themselves, they may have evolved a shell or a hard exoskeleton, but this is not always the case. • Bioactive metabolites have been isolated from many invertebrates among these are: • marine sponges, jellyfish, tunicates,bryozoans,sea hare and others. 6 kingdoms of marine organisms All kingdoms are represented in the marine environment, and most scientists classify marine organisms into one of the following 6 kingdoms. Bacteria are single-celled organisms that reproduce by splitting in two. Bacteria live throughout the marine environment. They play a crucial role in ecosystems, breaking down organic material and making nutrients available for the phytoplankton. Protozoans are single-celled organisms that are generally much larger than bacteria. They may be autotrophic or heterotrophic. In the marine environment, this kingdom is well represented and includes amoebae. Chromists range from very small organisms such as diatoms (a type of phytoplankton) to seaweeds. Most chromists photosynthesise but there are some significant differences that have led scientists to classify them separately to plants, for example, they use a different kind of chlorophyll. Fungi rely on breaking down organic material as they are not able to make their own food. There are very few fungi in the marine environment. Plants are multi-cellular and autotrophic – they use photosynthesis to produce food using sunlight. Plants are much more widespread on land and in freshwater, and there are only a few types that thrive in the marine environment, for example, eel grass and mangroves. Seaweeds were previously classed as plants before they were reclassified as chromists. Animals are typically large and multi-cellular. They are heterotrophic and rely on other organisms for food. Animals in the marine environment include jellyfish, sponges, sea spiders, bryozoans, mussels, sea stars, fish and whales.

11. Marine sponge: A probable treatment of breast cancer →الأخضر ده • Marine sponges: • They are sessile animals that filter water through their porous bodies. • They ingest food particles and dissolved materials. Marine sponges known to be a very rich source of terpenoids, halogenated alkaloids and Polyacetylenenic alcohols • Jellyfish: • They are free-swimming animal. • The body of the jellyfish consists of more than 95% of water and less than 5% of organic matter. • When removed from water, they collapse completely.

12. Tunicates: • Their body is a sack with two siphons through which water enters and exits. • Water is filtered inside the sack-shaped body.   • Bryozoans: • They are living for the most part in colonies of interconnected individuals.

13. البحر الأرنب • Sea hare: • The common name is derived from: - The two longrhinophores that project upwards from their heads → They resemble the ears of ahare

14. Biomedical potential of marine natural products: • In recent years, published reviews clearly indicate the tremendous potential of marine organisms as a source of new pharmaceuticals. • Classes of bioactive compounds include: Antiviral substances Cytotoxic compounds Antiparasitic compounds Anticoagulants

15. Classes of bioactive compounds include: (cont.) Antimicrobial agents Anti-inflammatory compounds Toxins

16. Some of the commercialized products

17. Vidarabine • Also known Ara-A • From sponge • Nucleoside it combines a adenosine base with an arabinose sugar • Antiviral (herpes virus)

18. cytarabine • also known as Ara-C (ArabinofuranosylCytidine). • From sponge • it combines a cytosine base with an arabinose sugar • Anticancer

19. Kainic acid • Anthelmintic • From seaweed

20. Ziconotide • From cone snail • Peptide • Analgesic

21. Eribulin • From sponge • Anticancer • Macrolide

22. Lovaza • From fish • Omega-3-fatty acid • Hypertriglyceride

23. Trabectedin • From tunicate • Alkaloid • Anticancer

24. Antiviral compounds • From sponge • The search for new antiviral agents from marine sources particularly sponges yielded several promising therapeutic leads. • Ara-A (Adenine arabinoside): • Vidarabineor Ara-A is a synthetic analogue of spongouridinewith improved antiviral activity. • Spongouridine isolated from the Caribbean sponge Tethyacrypta • Vidarabine is an inhibitor of viral DNA synthesis • Active against Herpes viruses

25. Antiviral • 2- Avarol and avarone • a sesquiterpenoidhydroquinone or quinone • isolated from the marine sponge Disideaavara • inhibitory effect • on the replication of the etiologic agent of Acquired Immune Deficiency Syndrome (AIDS) Avarone Avarol

26. Antiviral • From tunicate • 1- Patellazole B: • A thiazole-containing macrolide. • It showed very potent in vitro activity against Herpes simplex viruses. • It was isolated from the tunicate Lissoclinum patella.

27. Antiviral • 2- Didemnins • are cyclic depsipeptidecompounds • isolated from a tunicate (sea-squirt) of the genusTrididemnum • Active against herpes simplex virus type 1 • Didemnin B also showed antitumor activity

28. antiviral • 3- Eudistomins • Isolated from Eudistomaolivaceum • A family of β-carbolines

29. Antiviral • From seaweed • 1- sulphatedfucan • isolated from the brown seaweed Cystoseiraindica • Arepolysaccharide • have potent antiviral activity against herpes simplex virus types 1 • (HSV-1) and 2 (HSV-2)

30. Antiviral • 2- Sphingosinederivative • an 18-carbon amino alcohol