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Bioactive Compounds from Sponges (Phylum Porifera) Diversity of Sponge-Derived Compounds Manoalide: A Phospholipase A2 Inhibitor Bioactive Compounds from.

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Presentation on theme: "Bioactive Compounds from Sponges (Phylum Porifera) Diversity of Sponge-Derived Compounds Manoalide: A Phospholipase A2 Inhibitor Bioactive Compounds from."— Presentation transcript:

1 Bioactive Compounds from Sponges (Phylum Porifera) Diversity of Sponge-Derived Compounds Manoalide: A Phospholipase A2 Inhibitor Bioactive Compounds from Cnidarians Introduction to the Cnidaria Pseudoptersin: An Inhibitor of Eicosanoid Release Overview

2 Discodermolide Inhibits cell-division by stabilizing microtubules (i.e. inhibiting depolymerization) Anticancer drug (Clinical Phase II) Discodermia dissolute Drugs from the Sea: Sponges

3 Okadaic Acid l OA inhibits PP1 and PP2A sub-type of Ser/Thr Protein Phosphatases l Biomedical Research Tool Halichondria okadai Halichondrin B Drugs from the Sea: Sponges

4 Other Bioactive Compounds from Marine Sponges More than 5,300 sponge derived compounds (2000) …hundreds more discovered each year.

5 Other Bioactive Compounds from Marine Sponges Azothymidine (AZT), or Zidovudine Retrovir® Cytosine Arabinoside (Ara-C) Arabinose R = CH 3, Spongothymidine R = H, Spongouracil (from Cryptotethya crypta)

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7 Other Bioactive Compounds from Marine Sponges: Antiviral Antiviral Compounds from Sponges CompoundClassActivity Dragmacidin FIndole AlkaloidAntiviral Papuamides C, DCyclic PeptidesHIV-1 MololipidsTyramine LipidsHIV-1 Haplosamates A, BSulfamated SteroidHIV-1 Integrase Inhibitor Hamigeran BPhenolic MacrolideAntiviral - Herpes, Polio Weinbersterols A, BSulfated SterolsAntiviral - Feline Leukemia Variolin BAlkaloidAntiviral AvarolHydroquinone/UAG Suppressor SesquiterpeneGln tRNA Inhibitor “2’, 5’-A”2’,5’-NucleotideInterferon Mediator Hennoxazole ABisoxazoleAntiviral

8 Other Bioactive Compounds from Marine Sponges: Antimicrobial CompoundClassActivity Discodermins B, C, DCyclic PeptideAntibacterial TopsentiasterolSulfates Sulfated SterolAntibacterial/Antifungal Arenosclerins A, B, CAlkylpiperidineAntibacterial Axinellamines B-DImidazo-azolo-Antibacterial -imidazole alkaloid Acanthosterol I and JSulfated SterolAntifungal OceanapisideBiasminohydroxylipidAntifungal Glycoside SpongistatinPolyether Macrolide Antifungal Lactone Leucascandrolide AOxazole-Containing Antifungal Polyether Macrolide

9 Other Bioactive Compounds from Marine Sponges: “Antifouling” CompoundClass Kalihinene XIsocyanoterpenoid Kalihipyran BIsocyanoterpenoid 10  -FormarnidokalihinolIsocyanoterpenoid Pseudoeratidine 2Dibromopyrrole-Containing Spermidine Derivative Ceratinamide A and BBromotyrosine Derivative C22 CeramideCeramide FormosideTriterpene Glycoside, Sterol Diperoxide AxynyssimidesSesquiterpene Carbonimide Dichlorides

10 Other Bioactive Compounds from Marine Sponges: Anticancer CompoundClassActivity BRS1Diamino-dihydroxy-Protein Kinase C Inhibitor polyunsaturated lipid IsoaaptamineBenzonaphthyridine alkaloidProtein Kinase C Inhibitor Debromo-Pyrrole-Guanidine AlkaloidProtein Kinase C Inhibitor hymenialdisine AdociasulfatesTriterpenoid HydroquinoneKinesin Inhibitor LaulimalideMacrocyclic LactoneStabilization of Microtubules Peloruside AMacrocyclic LactoneStabilization of Microtubules HemiasterlinTripeptideStabilization of Microtubules DictyostatinMacrocyclic LactoneStabilization of Microtubules Spongistatin 1Bis{spiroacetal} MacrolideTubulin Polymerization Inhib. Halichondrin BPolyether MacrolideTubulin Polymerization Inhib. Arenastatin AMacrocyclic Lactan/LactoneTubulin Polymerization Inhib. Latrunculin AThiazole MacrolideActin-Depolymerization Neoamphi-Pyridoacridine AlkaloidTopoisomerase II Inhibitor medine Elenic AcidAlkylphenolTopoisomerase II Inhibitor Agelasphin  -GalactosylceramideNKT Cell Activator

11 Other Bioactive Compounds from Marine Sponges: Antiinflammatory CompoundClassMode of Action ManoalideCyclohexane Phospholipase A2 Inhibitor Sesterterpenoid Dysidotronic AcidDrimane Phospholipase A2 Inhibitor Sesquiterpenoid Ircinin-1 and -2Acyclic SesterterpenoidPhospholipase A2 Inhbitor PetrosaspongiolidesCheilantane Phospholipase A2 Inhibitor Spongidines A-dPyridinium AlkaloidPhospholipase A2 Inhibitor TopsentinBis-Indole AlkaloidPhospholipase A2 Inhibitor ScalaradialScalarane SesterterpenePhospholipase A2 Inhibitor Cacospongionolide BSesterterpene LactonePhospholipase A2 Inhibitor Jaspaquinol Diterpene BenzenoidLipoxygenase Inhibitor Subersic AcidDiterpene BenzenoidLipoxygenase Inhibitor

12 Discovery of Manoalide Luffariella variabilis Manoalide

13 Inflammation Assays (in vivo): e.g. Phorbol Myristate Acetate (PMA)-Induced Mouse Ear Edema PLA 2 Assays (in vitro): Exogenous PLA 2 - e.g. bee venom, cobra venom Antiinflammatory Assays

14 Phospholipids Arachidonate Phospholipids in Cell Membrane

15 PLA 2 Phospholipase-A 2 (PLA 2 ) Hydrolyzes Phospholids at sn-2 Position Arachidonic Acid Lysophospholipid

16 Catalytic Mechanism of PLA 2

17 Arachidonic Acid Leukotriene B4 (e.g.) Prostagalandin A2 (e.g.) Thromboxane B2 (e.g.) Cyclooxygenases-1 and -2 (COX-1 and -2) Lipoxygenases (LOX) Free Arachidonic Acid is Substrate for Eicosanoid Pathway

18 Eicosanoid Release Triggers Inflammation Response

19 Inflammation Response in Wound Healing

20 Inflammation Assays (in vivo): e.g. Phorbol Myristate Acetate (PMA)-Induced Mouse Ear Edema PLA 2 Assays (in vitro): Exogenous PLA 2 - e.g. bee venom, cobra venom Antiinflammatory Assays

21 PLA 2 from Bee Venom Radioassay Bee Venom Assay for PLA 2 Activity 3 H-Labeled Dipalmitoyl Phosphatidyl Choline 3 H-Labeled Palmitic Acid

22 Manoalide Inhibits PLA 2 Activity of Bee Venom Reynolds et al. (1991) J. Biol. Chem., 266:

23 PLA 2 Manoalide Irreversibly Inhibits PLA 2 Arachidonic Acid Lysophospholipid

24 Ring-Opening of Manoalide Creates Binding Sites Schiff’s Base Amide Michael Addition

25 Manoalide Binds Lysine Residues in PLA 2

26 Commerical Potential of Manoalide Licensed by Allergan® Pharmaceuticals Phase-I Clinical Trials for Treatment of Psoriasis Commercially Available Probe for PLA 2

27 Drugs from the Sea: Cnidaria Phylum Cnidaria Class Anthozoa “Sea Fans” “Sea Pens” “Corals”

28 Coral Biology Zooxanthellae = Symbiotic algae in coral Planula Corals are FOUNDATION of reefs

29 Coral Diseases “Bleaching” Microbial Infection Susceptible “Tolerant” Bioactive Compounds

30 Pseudopterogorgia elisabethae (“Purple Sea Whip”) Bioactive Compounds from Cnidarians: Pseudopterosin PsA R 1 =R 2 =R 3 =H PsB R 1 =Ac, R 2 =R 3 =H PsC R 2 =Ac, R 1 =R 3 =H PsD R 3 =Ac, R 1 =R 2 =H Look, Fenical, Jacobs and Clardy (1986) Proc. Natl. Acad. Sci., 83:

31 Pseudopterosin A Pseudopterosin A Inhibits Inflammation Response in Mouse Model Look, Fenical, Jacobs and Clardy (1986) Proc. Natl. Acad. Sci., 83:

32 Pseudopterosin A Pseudopterosin E Pseudopterosin A and E (PsA and PsE): Antiinflammatory Mechanism(s) Mayer et al. (1998) Life Sci., 62:

33 PsA and PsE Inhibit Mouse Ear Edema Mayer et al. (1998) Life Sci., 62:

34 PsA and PsE Inhibit PBQ- and Zymosan- Induced Writhing Mayer et al. (1998) Life Sci., 62:

35 PsE Inhibits Zymosan-Induced Peritoneal Prostaglandin and Leukotriene Exudate Mayer et al. (1998) Life Sci., 62:

36 PsA and PsE Inhibit Zymosan-Induced Release of Prostaglandin and Leukotriene from Murine Peritoneal Macrophages Mayer et al. (1998) Life Sci., 62:

37 Commerical Potential of Pseudopterosins Licensed to OsteoArthritis Sciences, Inc. Synthetic Derivative (Methopterosin) Completed Pre-Clinical Trials; Expected to Enter Phase-1 Clinical Trials as Topical Anti- Inflammatory for Dermatitis Cosmetic Ingredient

38 PsA R 1 =R 2 =R 3 =H PsB R 1 =Ac, R 2 =R 3 =H PsC R 2 =Ac, R 1 =R 3 =H PsD R 3 =Ac, R 1 =R 2 =H Seco-PsA R 1 =R 2 =R 3 =H Seco-PsB R 1 =Ac, R 2 =R 3 =H Seco-PsC R 2 =Ac, R 1 =R 3 =H Seco-PsD R 3 =Ac, R 1 =R 2 =H PsFPsYSeco-PsJ Pseudopterosins

39 5-Phosphomevalonate Mevalonate ATPADP Terpenoid Biosynthesis ATPADP Isopentyl Diphosphate + Dimethylallyl DiphosphateIsopentyl Diphosphate Geranyl Diphosphate “Isoprene”

40 Geranyl Diphosphate Terpenoid Biosynthesis LimoneneMenthol Monoterpenoids (C-10)

41 Farnesyl Diphosphate Geranyl Diphosphate Isopentyl Diphosphate (IPP) + Terpenoid Biosynthesis

42 Zingiberene Lanosterol Squalene “Steroids” (C-30) Sesquiterpenoids (C-15) Triterpenoids (C-30) Farnesyl Diphosphate Geranyl Diphosphate Isopentyl Diphosphate (IPP) + Terpenoid Biosynthesis

43 + IPP Farnesyl Diphosphate Geranyl Diphosphate Isopentyl Diphosphate (IPP) + Terpenoid Biosynthesis

44 (-)-Kaurene Diterpenoids (C-20) + IPP Farnesyl Diphosphate Geranyl Diphosphate Isopentyl Diphosphate (IPP) + Terpenoid Biosynthesis

45 + IPP Farnesyl Diphosphate Geranyl Diphosphate Isopentyl Diphosphate (IPP) + Terpenoid Biosynthesis Sesterterpenoids (C-25) + IPP

46 Manoalide is a Sesterterpene

47 Biosynthesis of Pseudopterosins GGPP ElisabethatrieneErogorgiaene


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