Potencial de los productos naturales marinos como agentes anticáncer: La situación de Panamá

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1 RIBECACER Potencial de los productos naturales marinos como agentes anticáncer: La situación de Panamá VIII Simposio Iberoamericano de plantas medicinales y III Simposio Iberoamericano de investigación en cáncer Marcelino Gutiérrez-Guevara Itajai, ctubre 2016 M. Gutiérrez, IDICASAT-AIP

2 Talk verview 1. Marine biodiversity and natural products 2. Marine natural products in the market 3. The role of symbiotic bacteria in drug discovery 4. Marine Biodiversity of Panama 5. Study of Marine atural Products from Panama 6. Concluding remarks M. Gutiérrez, IDICASAT-AIP

3 Why to search for new drugs in the oceans? M. Gutiérrez, IDICASAT-AIP

4 ceans cover over 70 % of earth surface

5 Why Marine rganisms? Life started in the oceans There are 11 terrestrial phyla and 28 marine phyla -15 are exclusively marine Marine ecosystems are still a unexplored frontier specially deep-sea and polar regions which comprise 95% of the biosphere Sessile organisms have evolved developing powerful chemical defenses against predators owadays we have more access to the marine biodiversity (SCUBA, Submarines)

6 Marine rganisms are a rich source of natural products Sponges Cnidarians Ascidians Echinoderms Mollusks Microorganisms Cyanobacteria Bryozoans

7 Marine organisms have provided more than 20,000 compounds over last 50 years All main types of natural products found in land can be found in marine environments More than 500 new compounds/year were isolated from marine sources over the last decade, and about 1000 were reported since 2008 to the present. Several terpenoid-carbon skeletons are exclusively marine

8 What happened with all these marine compounds?

9 Stories of success: There are seven MP in the market! and four in cancer

10 Status: FDA Approved Cytarabine (Ara-C) 2 Criptotethya crypta Arabinofuranosyl Cytosine Ara-C, MP derivative Approved 1969 Spongouridine MP Isolated in early 50s Source: Sponge (Criptotethya crypta) Disease area: Acute myeloid leukemia and non-odgkin lymphoma. Molecular target: DA polimerase

11 Status: FDA Approved Trabactedin (ET743) S Ac Ecteinascidin-743 (Yondelis ) Ecteinascidia turbinata Isolated 1986 Approved 2007 There was gap of 38 years in anticancer MP drug discovery! Source: Tunicate (Ecteinascidia turbinata) Disease area: Soft tissue sarcoma and ovarian cancer Molecular target: Minor groove of DA

12 Status: FDA Approved Eribulin Mesylate (alaven) 2 alichondrin B E7389 (Eribulin) Isolated in 1986 (32 stereocenters) Marketed in 2010 (19 stereocenters) Source: Sponge (alichondria okadai) Disease area: Late stage matastatic breast cancer Molecular target: Microtubules

13 Status: FDA Approved Brentuximab vedotin (SG-35) Abm S Monomethylauristatin E 2 S Approved 2011 Dolastatin 10 Isolated in 1987 Source: Mollusk (Dolabella auricularia) Disease area: odgkin s lymphoma, anaplastic large cell lymphoma Molecular target: CD30 and microtubules

14 Study of symbiotic systems as resource for drug discovery

15 ew genomics developments and modern analytical instrumentation allow us to see symbiosis with new eyes

16 Microbes form associations with all organisms. For each human cell, we have an estimated of 10 microbial cells This is equivalent to 100 trillons of microbes inhabitant our body

17 Same chemotype from organisms so distant? Theonella swinhoei Paederus sp.

18 Entotheonella sp. is responsible for the natural product families isolated from the sponge Theonella swinhoei Wilson, M.C., et al., ature, 2014, doi: /nature12959

19 Yondelis S Eitenascidia turbinata Soft tissue sarcoma and ovarian cancer

20 S Candidatus Endoecteinascidia frumentensis C 2 2 Streptomyces lavendulae Myxococcus xanthus Pseudomonas fluorescens Rath, C. M. et al., ACS Chem. Biol. 2011, 6,

21 Marine atural products and MP derivatives that are FDA approved are most likely produced by microorganisms Compound name Collected source organisms Predicted biosynthetic source Disease area Cytarabine (Ara-C) Sponge Bacterium Cancer Eribulin Mesylate Sponge Bacterium Cancer Trabactedin (Yondelis) Tunicate Bacterium Cancer Brentuximab vedotin Mollusk Cyanobacterium Cancer Virabidine (Ara-A) Sponge Bacterium Antiviral Ziconotide Cone Snail Mollusk Pain mega-3-acid ethyl esters Fish Microalgae ypertrigliceridemia Gerwick, W..; Moore, B.S. Chemistry & Biology 2012, 19,

22 Gerwick, W..; Moore, B.S. Chemistry & Biology 2012, 19,

23 Marine Biodiversity of Panama

24 Panama s marine biodiversity M. Gutiérrez, IDICASAT-AIP

25 Formation of Panamanian Isthmus Robertson, R. et al. Smithsonian Contribution to the Marine Sciences, 2009, 18, 73-93

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27 Zones with high marine biodiversity hot spots Yellow = poor species richness/ orange = rich/ red = very rich/ dark red = regions with high number of endemic species(= hotspots)

28 Coiba ational Park World heritage site igh level of biological diversity igh level of endemism

29 2701 Km2

30 What is the status of MP in Panama

31 rganisms Studied in Panama Corals Cyanobacteria Bacteria Mollusks Sponges

32 Compounds isolated per year

33 ew compounds (in blue) isolated per year

34 Compounds isolated per taxa Sponges Mollusks Macroalgae Fungy Cyanobacteria Corals Bacteria

35 Bioactivity of Panamanian compounds Antimicrobial Anti-inflammatory Anticancer Antiprotozoal

36 Anticancer compounds Coibamide A Belamide A IC um CT-116 colon

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38 Concluding remarks Panama possesses an amazing marine biological diversity awaiting to be explored. Five Marine protected areas provide a safe environment for scientific research. Panamanian marine organism have proven to be a good source of new and active compounds. Marine natural products research in Panama represents a great and unique opportunity for drug discovery.

39 brigado