? Bioactive Compounds from Sponges (Phylum Porifera)

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Overview
? 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
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Drugs from the Sea Sponges
? Inhibits cell-division by stabilizing
microtubules (i.e. inhibiting depolymerization)
? Anticancer drug (Clinical Phase II)
Discodermia dissolute
Discodermolide
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Drugs from the Sea Sponges
Halichondrin B
Okadaic Acid
Halichondria okadai

• OA inhibits PP1 and PP2A sub-type of Ser/Thr
  Protein Phosphatases
• Biomedical Research Tool

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Other Bioactive Compounds from Marine Sponges
More than 5,300 sponge derived compounds
(2000) hundreds more discovered each year.
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Other Bioactive Compounds from Marine Sponges
R CH3, Spongothymidine R H,
Spongouracil (from Cryptotethya crypta)
Arabinose
Retrovir
Cytosine Arabinoside (Ara-C)
Azothymidine (AZT), or Zidovudine
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(No Transcript)
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Other Bioactive Compounds from Marine Sponges
Antiviral
Antiviral Compounds from Sponges Compound Class
Activity Dragmacidin F Indole
Alkaloid Antiviral Papuamides C, D Cyclic
Peptides HIV-1 Mololipids Tyramine
Lipids HIV-1 Haplosamates A, B Sulfamated
Steroid HIV-1 Integrase Inhibitor Hamigeran
B Phenolic Macrolide Antiviral - Herpes,
Polio Weinbersterols A, B Sulfated
Sterols Antiviral - Feline Leukemia Variolin
B Alkaloid Antiviral Avarol Hydroquinone/ UA
G Suppressor Sesquiterpene Gln tRNA
Inhibitor 2, 5-A 2,5-Nucleotide Interferon
Mediator Hennoxazole A Bisoxazole Antiviral
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Other Bioactive Compounds from Marine Sponges
Antimicrobial
Compound Class Activity Discodermins B, C,
D Cyclic Peptide Antibacterial TopsentiasterolSul
fates Sulfated Sterol Antibacterial/Antifungal A
renosclerins A, B , C Alkylpiperidine Antibacteri
al Axinellamines B-D Imidazo-azolo- Antibacterial
-imidazole alkaloid Acanthosterol I and
J Sulfated Sterol Antifungal Oceanapiside Biasmi
nohydroxylipid Antifungal Glycoside Spongista
tin Polyether Macrolide Antifungal
Lactone Leucascandrolide A Oxazole-Containing
Antifungal Polyether Macrolide
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Other Bioactive Compounds from Marine Sponges
Antifouling
Compound Class Kalihinene X Isocyanoterpenoi
d Kalihipyran B Isocyanoterpenoid 10 b
-Formarnidokalihinol Isocyanoterpenoid Pseudoerati
dine 2 Dibromopyrrole-Containing
Spermidine Derivative Ceratinamide A and
B Bromotyrosine Derivative C22
Ceramide Ceramide Formoside Triterpene
Glycoside, Sterol Diperoxide Axynyssimides
Sesquiterpene Carbonimide Dichlorides
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Other Bioactive Compounds from Marine Sponges
Anticancer
Compound Class Activity BRS1 Diamino-dihydro
xy- Protein Kinase C Inhibitor polyunsaturated
lipid Isoaaptamine Benzonaphthyridine
alkaloid Protein Kinase C Inhibitor Debromo- Pyrro
le-Guanidine Alkaloid Protein Kinase C Inhibitor
hymenialdisine Adociasulfates Triterpenoid
Hydroquinone Kinesin Inhibitor Laulimalide Macrocy
clic Lactone Stabilization of Microtubules Peloru
side A Macrocyclic Lactone Stabilization of
Microtubules Hemiasterlin Tripeptide Stabilizati
on of Microtubules Dictyostatin Macrocyclic
Lactone Stabilization of Microtubules Spongistati
n 1 Bisspiroacetal Macrolide Tubulin
Polymerization Inhib. Halichondrin B Polyether
Macrolide Tubulin Polymerization
Inhib. Arenastatin A Macrocyclic
Lactan/Lactone Tubulin Polymerization
Inhib. Latrunculin A Thiazole Macrolide Actin-Dep
olymerization Neoamphi- Pyridoacridine
Alkaloid Topoisomerase II Inhibitor
medine Elenic Acid Alkylphenol Topoisomerase II
Inhibitor Agelasphin a-Galactosylceramide NKT
Cell Activator
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Other Bioactive Compounds from Marine Sponges
Antiinflammatory
Compound Class Mode of Action Manoalide Cycloh
exane Phospholipase A2 Inhibitor
Sesterterpenoid Dysidotronic Acid Drimane
Phospholipase A2 Inhibitor
Sesquiterpenoid Ircinin-1 and -2 Acyclic
Sesterterpenoid Phospholipase A2
Inhbitor Petrosaspongiolides Cheilantane
Phospholipase A2 Inhibitor Spongidines
A-d Pyridinium Alkaloid Phospholipase A2
Inhibitor Topsentin Bis-Indole
Alkaloid Phospholipase A2 Inhibitor Scalaradial S
calarane Sesterterpene Phospholipase A2
Inhibitor Cacospongionolide B Sesterterpene
Lactone Phospholipase A2 Inhibitor Jaspaquinol
Diterpene Benzenoid Lipoxygenase
Inhibitor Subersic Acid Diterpene
Benzenoid Lipoxygenase Inhibitor
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Discovery of Manoalide
Luffariella variabilis
Manoalide
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Antiinflammatory Assays
Inflammation Assays (in vivo) e.g. Phorbol
Myristate Acetate (PMA)-Induced Mouse Ear
Edema PLA2 Assays (in vitro) Exogenous PLA2
- e.g. bee venom, cobra venom
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Phospholipids in Cell Membrane
Phospholipids
Arachidonate
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Phospholipase-A2 (PLA2) Hydrolyzes Phospholids at
sn-2 Position
PLA2
Arachidonic Acid
Lysophospholipid
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Catalytic Mechanism of PLA2
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Free Arachidonic Acid is Substrate for Eicosanoid
Pathway
Arachidonic Acid
Cyclooxygenases-1 and -2 (COX-1 and -2)
Lipoxygenases (LOX)
Prostagalandin A2 (e.g.)
Leukotriene B4 (e.g.)
Thromboxane B2 (e.g.)
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Eicosanoid Release Triggers Inflammation Response
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Inflammation Response in Wound Healing
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Antiinflammatory Assays
Inflammation Assays (in vivo) e.g. Phorbol
Myristate Acetate (PMA)-Induced Mouse Ear
Edema PLA2 Assays (in vitro) Exogenous PLA2
- e.g. bee venom, cobra venom
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Bee Venom Assay for PLA2 Activity
3H-Labeled Dipalmitoyl Phosphatidyl Choline
PLA2 from Bee Venom
3H-Labeled Palmitic Acid
Radioassay
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Manoalide Inhibits PLA2 Activity of Bee Venom
Reynolds et al. (1991) J. Biol. Chem., 266
16512-7
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Manoalide Irreversibly Inhibits PLA2
PLA2
Arachidonic Acid
Lysophospholipid
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Ring-Opening of Manoalide Creates Binding Sites
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Manoalide Binds Lysine Residues in PLA2
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Commerical Potential of Manoalide
? Licensed by Allergan Pharmaceuticals ?
Phase-I Clinical Trials for Treatment of
Psoriasis ? Commercially Available Probe for
PLA2
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Drugs from the Sea Cnidaria
Phylum Cnidaria
Class Anthozoa
Sea Pens
Corals
Sea Fans
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Coral Biology
? Corals are FOUNDATION of reefs
Zooxanthellae Symbiotic algae in coral
Planula
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Coral Diseases
Bleaching
Tolerant
Susceptible
Microbial Infection
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Bioactive Compounds from Cnidarians
Pseudopterosin
PsA R1R2R3H PsB R1Ac, R2R3H PsC R2Ac,
R1R3H PsD R3Ac, R1R2H
Pseudopterogorgia elisabethae (Purple Sea Whip)
Look, Fenical, Jacobs and Clardy (1986) Proc.
Natl. Acad. Sci., 83 6238-40
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Pseudopterosin A Inhibits Inflammation Response
in Mouse Model
Pseudopterosin A
Look, Fenical, Jacobs and Clardy (1986) Proc.
Natl. Acad. Sci., 83 6238-40
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Pseudopterosin A and E (PsA and PsE)
Antiinflammatory Mechanism(s)
Pseudopterosin A
Pseudopterosin E
Mayer et al. (1998) Life Sci., 62 401-407
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PsA and PsE Inhibit Mouse Ear Edema
Mayer et al. (1998) Life Sci., 62 401-407
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PsA and PsE Inhibit PBQ- and Zymosan-Induced
Writhing
Mayer et al. (1998) Life Sci., 62 401-407
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PsE Inhibits Zymosan-Induced Peritoneal
Prostaglandin and Leukotriene Exudate
Mayer et al. (1998) Life Sci., 62 401-407
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PsA and PsE Inhibit Zymosan-Induced Release of
Prostaglandin and Leukotriene from Murine
Peritoneal Macrophages
Mayer et al. (1998) Life Sci., 62 401-407
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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
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Pseudopterosins
PsA R1R2R3H PsB R1Ac, R2R3H PsC R2Ac,
R1R3H PsD R3Ac, R1R2H
Seco-PsA R1R2R3H Seco-PsB R1Ac,
R2R3H Seco-PsC R2Ac, R1R3H Seco-PsD R3Ac,
R1R2H
PsF
PsY
Seco-PsJ
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Terpenoid Biosynthesis
Mevalonate
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Terpenoid Biosynthesis
Geranyl Diphosphate
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Terpenoid Biosynthesis
Geranyl Diphosphate
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Terpenoid Biosynthesis
Geranyl Diphosphate
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Terpenoid Biosynthesis
Geranyl Diphosphate
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Terpenoid Biosynthesis
Geranyl Diphosphate
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Terpenoid Biosynthesis
Geranyl Diphosphate
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Manoalide is a Sesterterpene
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Biosynthesis of Pseudopterosins
Elisabethatriene
Erogorgiaene
GGPP