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
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
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
Other Bioactive Compounds from Other Bioactive Compounds from Marine SpongesMarine Sponges
More than 5,300 sponge derived compounds (2000)
…hundreds more discovered each year.
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-
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
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
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
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
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
Discovery of ManoalideLuffariella variabilis
O
O
OHO
HO
Manoalide
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
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
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
Catalytic Mechanism of PLACatalytic Mechanism of PLA22
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
Eicosanoid Release Triggers Eicosanoid Release Triggers Inflammation ResponseInflammation Response
Inflammation Response in Wound Inflammation Response in Wound HealingHealing
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
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
Manoalide Inhibits PLAManoalide Inhibits PLA22 Activity of Activity of
Bee VenomBee Venom
Reynolds et al. (1991) J. Biol. Chem., 266: 16512-7
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
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
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
Commerical Potential of ManoalideCommerical Potential of Manoalide
Licensed by Allergan® Pharmaceuticals
Phase-I Clinical Trials for Treatment of Psoriasis
Commercially Available Probe for PLA2
Drugs from the Sea: CnidariaPhylum Cnidaria
Class Anthozoa
“Sea Fans”
“Sea Pens”
“Corals”
Coral BiologyCoral Biology
Zooxanthellae = Symbiotic algae in coral
Planula
Corals are FOUNDATION of reefs
Coral DiseasesCoral Diseases
“Bleaching”
Microbial InfectionSusceptible
“Tolerant”
Bioactive Compounds
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
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
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
PsA and PsE Inhibit Mouse Ear EdemaPsA and PsE Inhibit Mouse Ear Edema
Mayer et al. (1998) Life Sci., 62: 401-407
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
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
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
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
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
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”
OP
O
O-
OP
O
-O
O-Geranyl Diphosphate
Terpenoid BiosynthesisTerpenoid Biosynthesis
OH
Limonene Menthol
Monoterpenoids(C-10)
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
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
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
(-)-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
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
O
O
OHO
HO
Manoalide is a SesterterpeneManoalide is a Sesterterpene
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