Bioactive Compounds from Sponges (Phylum Porifera) Diversity of Sponge-Derived Compounds Manoalide:...
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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
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OO
OH
HO
OH O NH2
O
Discodermolide
Inhibits cell-division by stabilizing microtubules (i.e. inhibiting depolymerization)
Anticancer drug (Clinical Phase II)
Discodermia dissolute
Drugs from the Sea: SpongesDrugs from the Sea: Sponges
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Okadaic Acid
OA inhibits PP1 and PP2A sub-type of Ser/Thr Protein Phosphatases
Biomedical Research Tool
Halichondria okadai
HO
O
O O
O
O O
O
O
CH3
CH3H
CH3
H
HOH
OH
H
OH
H3C OH
H3C
HO
O
HO
HO
OO
O
O
O
O
O
OO
O
O
O
OOO
H
H
H
H
H
H
H
H
Halichondrin B
Drugs from the Sea: SpongesDrugs from the Sea: Sponges
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Other Bioactive Compounds from Other Bioactive Compounds from Marine SpongesMarine Sponges
More than 5,300 sponge derived compounds (2000)
…hundreds more discovered each year.
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Other Bioactive Compounds from Other Bioactive Compounds from Marine SpongesMarine Sponges
Azothymidine (AZT), or Zidovudine
Retrovir®Cytosine
Arabinoside(Ara-C)
O
N
HN
O
OH
O
R
HO
OH
Arabinose
O
N
N
O
OH
NH2
HO
OH
R = CH3, SpongothymidineR = H, Spongouracil
(from Cryptotethya crypta)
O
N
HN
O
N
O
CH3
HO
N+
N-
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Other Bioactive Compounds from Other Bioactive Compounds from Marine Sponges: Marine Sponges: AntiviralAntiviral
Antiviral Compounds from Sponges
Compound Class ActivityDragmacidin F Indole Alkaloid AntiviralPapuamides C, D Cyclic Peptides HIV-1Mololipids Tyramine Lipids HIV-1Haplosamates A, B Sulfamated Steroid HIV-1 Integrase InhibitorHamigeran B Phenolic Macrolide Antiviral - Herpes, PolioWeinbersterols A, B Sulfated Sterols Antiviral - Feline LeukemiaVariolin B Alkaloid AntiviralAvarol Hydroquinone/ UAG Suppressor
Sesquiterpene Gln tRNA Inhibitor“2’, 5’-A” 2’,5’-Nucleotide Interferon MediatorHennoxazole A Bisoxazole Antiviral
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Other Bioactive Compounds from Other Bioactive Compounds from Marine Sponges: Marine Sponges: AntimicrobialAntimicrobial
Compound Class ActivityDiscodermins B, C, D Cyclic Peptide AntibacterialTopsentiasterolSulfates Sulfated Sterol Antibacterial/AntifungalArenosclerins A, B , C Alkylpiperidine AntibacterialAxinellamines B-D Imidazo-azolo- Antibacterial
-imidazole alkaloidAcanthosterol I and J Sulfated Sterol AntifungalOceanapiside Biasminohydroxylipid Antifungal
GlycosideSpongistatin Polyether Macrolide Antifungal
LactoneLeucascandrolide A Oxazole-Containing Antifungal
Polyether Macrolide
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Other Bioactive Compounds from Other Bioactive Compounds from Marine Sponges: Marine Sponges: “Antifouling”“Antifouling”
Compound ClassKalihinene X IsocyanoterpenoidKalihipyran B Isocyanoterpenoid10 -Formarnidokalihinol IsocyanoterpenoidPseudoeratidine 2 Dibromopyrrole-Containing
Spermidine DerivativeCeratinamide A and B Bromotyrosine DerivativeC22 Ceramide CeramideFormoside Triterpene Glycoside,
Sterol DiperoxideAxynyssimides Sesquiterpene Carbonimide
Dichlorides
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Other Bioactive Compounds from Other Bioactive Compounds from Marine Sponges: Marine Sponges: AnticancerAnticancer
Compound Class ActivityBRS1 Diamino-dihydroxy- Protein Kinase C Inhibitor
polyunsaturated lipidIsoaaptamine Benzonaphthyridine alkaloid Protein Kinase C InhibitorDebromo- Pyrrole-Guanidine Alkaloid Protein Kinase C Inhibitor hymenialdisineAdociasulfates Triterpenoid Hydroquinone Kinesin InhibitorLaulimalide Macrocyclic Lactone Stabilization of MicrotubulesPeloruside A Macrocyclic Lactone Stabilization of MicrotubulesHemiasterlin Tripeptide Stabilization of MicrotubulesDictyostatin Macrocyclic Lactone Stabilization of MicrotubulesSpongistatin 1 Bis{spiroacetal} Macrolide Tubulin Polymerization Inhib.Halichondrin B Polyether Macrolide Tubulin Polymerization Inhib.Arenastatin A Macrocyclic Lactan/Lactone Tubulin Polymerization Inhib.Latrunculin A Thiazole Macrolide Actin-DepolymerizationNeoamphi- Pyridoacridine Alkaloid Topoisomerase II Inhibitor medineElenic Acid Alkylphenol Topoisomerase II InhibitorAgelasphin -Galactosylceramide NKT Cell Activator
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Other Bioactive Compounds from Other Bioactive Compounds from Marine Sponges: Marine Sponges: AntiinflammatoryAntiinflammatory
Compound Class Mode of ActionManoalide Cyclohexane Phospholipase A2 Inhibitor
SesterterpenoidDysidotronic Acid Drimane Phospholipase A2 Inhibitor
SesquiterpenoidIrcinin-1 and -2 Acyclic Sesterterpenoid Phospholipase A2 InhbitorPetrosaspongiolides Cheilantane Phospholipase A2 InhibitorSpongidines A-d Pyridinium Alkaloid Phospholipase A2 InhibitorTopsentin Bis-Indole Alkaloid Phospholipase A2 InhibitorScalaradial Scalarane Sesterterpene Phospholipase A2 InhibitorCacospongionolide B Sesterterpene Lactone Phospholipase A2 InhibitorJaspaquinol Diterpene Benzenoid Lipoxygenase InhibitorSubersic Acid Diterpene Benzenoid Lipoxygenase Inhibitor
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Discovery of ManoalideLuffariella variabilis
O
O
OHO
HO
Manoalide
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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
Antiinflammatory Assays
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H2C
CHO
H2C
O
OO
R2
O
P
O
O-
O X
H2C
CHO
H2C
O
OO
R1
R2
O
P
O
O-
O X
Phospholipids
Arachidonate
Phospholipids in Cell MembranePhospholipids in Cell Membrane
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H2C
CHO
H2C
O
OO
R2
O
P
O
O-
O X
COOH
PLA2
Phospholipase-APhospholipase-A22 (PLA (PLA22) Hydrolyzes ) Hydrolyzes
Phospholids at Phospholids at sn-2 sn-2 PositionPosition
H2C
CHHO
H2C
O
O
R2
O
P
O
O-
O X
Arachidonic AcidLysophospholipid
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Catalytic Mechanism of PLACatalytic Mechanism of PLA22
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COOH
COOH
OH
O
HO
OHO
OH
COO-
OH
OH
OH
COOH
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 Free Arachidonic Acid is Substrate for Eicosanoid PathwayEicosanoid Pathway
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Eicosanoid Release Triggers Eicosanoid Release Triggers Inflammation ResponseInflammation Response
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Inflammation Response in Wound Inflammation Response in Wound HealingHealing
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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
Antiinflammatory Assays
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PLA2 from Bee Venom
Radioassay
Bee Venom Assay for PLABee Venom Assay for PLA22 Activity Activity
3H-Labeled Dipalmitoyl Phosphatidyl Choline
3H-Labeled Palmitic Acid
O
O
CH2
CHO
O
H2C
O P
O
O-
O
N+
CH3
CH3
CH3
3H
3H3H
3H
3H3H
O
3H
3H3H OH
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Manoalide Inhibits PLAManoalide Inhibits PLA22 Activity of Activity of
Bee VenomBee Venom
Reynolds et al. (1991) J. Biol. Chem., 266: 16512-7
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H2C
CHO
H2C
O
OO
R2
O
P
O
O-
O X
COOH
PLA2
Manoalide Irreversibly Inhibits PLAManoalide Irreversibly Inhibits PLA22
H2C
CHHO
H2C
O
O
R2
O
P
O
O-
O X
Arachidonic AcidLysophospholipid
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O
CH
OHO
O
OH
CH
O
OH
O
O
HO
O
O
OHO
HO
CHO
OH
CH
O
O
OH
Ring-Opening of Manoalide Creates Ring-Opening of Manoalide Creates Binding SitesBinding Sites
Schiff’s BaseAmide
Michael Addition
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CH
N
OH
CH
O
N
OH
LysLys
O
O
OHO
HO
O
CH
OHO
N
OH
Lys
Manoalide Binds Lysine Residues in PLAManoalide Binds Lysine Residues in PLA22
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Commerical Potential of ManoalideCommerical 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: CnidariaPhylum Cnidaria
Class Anthozoa
“Sea Fans”
“Sea Pens”
“Corals”
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Coral BiologyCoral Biology
Zooxanthellae = Symbiotic algae in coral
Planula
Corals are FOUNDATION of reefs
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Coral DiseasesCoral Diseases
“Bleaching”
Microbial InfectionSusceptible
“Tolerant”
Bioactive Compounds
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Pseudopterogorgia elisabethae
(“Purple Sea Whip”)
Bioactive Compounds from Cnidarians: Bioactive Compounds from Cnidarians: PseudopterosinPseudopterosin
O
OH
O
OR3
R2O
R1O
PsA R1=R2=R3=HPsB R1=Ac, R2=R3=HPsC R2=Ac, R1=R3=HPsD R3=Ac, R1=R2=H
Look, Fenical, Jacobs and Clardy (1986) Proc. Natl. Acad. Sci., 83: 6238-40
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O
OH
OOH
HO
HO
Pseudopterosin A
Pseudopterosin A Inhibits Inflammation Pseudopterosin A Inhibits Inflammation Response in Mouse ModelResponse in Mouse Model
Look, Fenical, Jacobs and Clardy (1986) Proc. Natl. Acad. Sci., 83: 6238-40
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OH
O
O
OH
OH
OH
O
OH
O
OH
HO
HO
Pseudopterosin A
Pseudopterosin E
Pseudopterosin A and E (PsA and PsE): Pseudopterosin A and E (PsA and PsE): Antiinflammatory Mechanism(s)Antiinflammatory Mechanism(s)
Mayer et al. (1998) Life Sci., 62: 401-407
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PsA and PsE Inhibit Mouse Ear EdemaPsA 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-PsA and PsE Inhibit PBQ- and Zymosan-Induced WrithingInduced Writhing
Mayer et al. (1998) Life Sci., 62: 401-407
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PsE Inhibits Zymosan-Induced Peritoneal PsE Inhibits Zymosan-Induced Peritoneal Prostaglandin and Leukotriene ExudateProstaglandin and Leukotriene Exudate
Mayer et al. (1998) Life Sci., 62: 401-407
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PsA and PsE Inhibit Zymosan-Induced PsA and PsE Inhibit Zymosan-Induced Release of Prostaglandin and Release of Prostaglandin and
Leukotriene from Murine Peritoneal Leukotriene from Murine Peritoneal MacrophagesMacrophages
Mayer et al. (1998) Life Sci., 62: 401-407
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Commerical Potential of PseudopterosinsCommerical 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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O
OH
O
OR3
R2O
R1O
OH
O
O
HO
HO
OH
OH
O
O
HO
HO
OH
O
OH
O
OR3
R2O
R1O
OH
O
O
HO
HO
OH
PsA R1=R2=R3=HPsB R1=Ac, R2=R3=HPsC R2=Ac, R1=R3=HPsD R3=Ac, R1=R2=H
Seco-PsA R1=R2=R3=HSeco-PsB R1=Ac, R2=R3=HSeco-PsC R2=Ac, R1=R3=HSeco-PsD R3=Ac, R1=R2=H
PsF PsY Seco-PsJ
PseudopterosinsPseudopterosins
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HO
COO-
OH
O
COO-
OH
P
O
O-
OP
O
-O
O-
5-Phosphomevalonate
Mevalonate
ATP ADP
Terpenoid BiosynthesisTerpenoid BiosynthesisATP ADP
Isopentyl Diphosphate
OP
O
O-
OP
O
-O
O-
OP
O
O-
OP
O
-O
O- H
OP
O
O-
OP
O
-O
O-
+
Dimethylallyl DiphosphateIsopentyl Diphosphate
OP
O
O-
OP
O
-O
O-
Geranyl Diphosphate
OP
O
O-
OP
O
-O
O-
“Isoprene”
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OP
O
O-
OP
O
-O
O-Geranyl Diphosphate
Terpenoid BiosynthesisTerpenoid Biosynthesis
OH
Limonene Menthol
Monoterpenoids(C-10)
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OP
O
O-
OP
O
-O
O-
Farnesyl Diphosphate
OP
O
O-
OP
O
-O
O-Geranyl Diphosphate
Isopentyl Diphosphate(IPP)
OP
O
O-
OP
O
-O
O- H
+
Terpenoid BiosynthesisTerpenoid Biosynthesis
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HO
Zingiberene
Lanosterol
Squalene
“Steroids”(C-30)
Sesquiterpenoids (C-15)
Triterpenoids(C-30)
OP
O
O-
OP
O
-O
O-
Farnesyl Diphosphate
OP
O
O-
OP
O
-O
O-Geranyl Diphosphate
Isopentyl Diphosphate(IPP)
OP
O
O-
OP
O
-O
O- H
+
Terpenoid BiosynthesisTerpenoid Biosynthesis
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OP
O
O-
OP
O
-O
O-
+ IPPOP
O
O-
OP
O
-O
O-
Farnesyl Diphosphate
OP
O
O-
OP
O
-O
O-Geranyl Diphosphate
Isopentyl Diphosphate(IPP)
OP
O
O-
OP
O
-O
O- H
+
Terpenoid BiosynthesisTerpenoid Biosynthesis
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(-)-Kaurene
Diterpenoids(C-20)
OP
O
O-
OP
O
-O
O-
+ IPPOP
O
O-
OP
O
-O
O-
Farnesyl Diphosphate
OP
O
O-
OP
O
-O
O-Geranyl Diphosphate
Isopentyl Diphosphate(IPP)
OP
O
O-
OP
O
-O
O- H
+
Terpenoid BiosynthesisTerpenoid Biosynthesis
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OP
O
O-
OP
O
-O
O-
+ IPPOP
O
O-
OP
O
-O
O-
Farnesyl Diphosphate
OP
O
O-
OP
O
-O
O-Geranyl Diphosphate
Isopentyl Diphosphate(IPP)
OP
O
O-
OP
O
-O
O- H
+
Terpenoid BiosynthesisTerpenoid Biosynthesis
Sesterterpenoids (C-25)
OP
O
O-
OP
O
-O
O-
+ IPP
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O
O
OHO
HO
Manoalide is a SesterterpeneManoalide is a Sesterterpene
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Biosynthesis of Pseudopterosins
OPP
GGPP
H HH
H
OH
H
OH
OH
H
O
OH
OHO
HO
OH
H
O
OH
OHO
HO
OH
Elisabethatriene Erogorgiaene