Download Bioactive Compounds from Sponges

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
Drugs from the Sea: Sponges
 Inhibits cell-division by
stabilizing microtubules
(i.e. inhibiting
depolymerization)
 Anticancer drug
Discodermia dissolute
(Clinical Phase II)
HO
O
O
OH
O
NH2
O
OH
Discodermolide
Drugs from the Sea: Sponges
Halichondrin B
Okadaic Acid
Halichondria okadai
H
O
H
O
O
O
O
O
H
CH3
O
O
OH
O
H
H
O
O
O
H
O
H
O
H3C
O
H
HO
H3C
OH
O
OH
O
O
CH3
O
HO
O
O
H
H
OH
CH3
H
H
HO
HO
 OA inhibits PP1 and PP2A sub-type of Ser/Thr
Protein Phosphatases
 Biomedical Research Tool
O
O
O
Other Bioactive Compounds from
Marine Sponges
More than 5,300 sponge derived compounds (2000)
…hundreds more discovered each year.
Other Bioactive Compounds from
Marine Sponges
O
R
HN
Arabinose
HO
O
N
R = CH3, Spongothymidine
R = H, Spongouracil
(from Cryptotethya crypta)
O
OH
O
CH 3
NH2
HN
OH
N
HO
HO
O
O
N
O
N
Retrovir®
O
OH
OH
Cytosine
Arabinoside
(Ara-C)
N
N+
N-
Azothymidine (AZT), or
Zidovudine
Other Bioactive Compounds from
Marine Sponges: Antiviral
Antiviral Compounds from Sponges
Compound
Dragmacidin F
Papuamides C, D
Mololipids
Haplosamates A, B
Hamigeran B
Weinbersterols A, B
Variolin B
Avarol
“2’, 5’-A”
Hennoxazole A
Class
Indole Alkaloid
Cyclic Peptides
Tyramine Lipids
Sulfamated Steroid
Phenolic Macrolide
Sulfated Sterols
Alkaloid
Hydroquinone/
Sesquiterpene
2’,5’-Nucleotide
Bisoxazole
Activity
Antiviral
HIV-1
HIV-1
HIV-1 Integrase Inhibitor
Antiviral - Herpes, Polio
Antiviral - Feline Leukemia
Antiviral
UAG Suppressor
Gln tRNA Inhibitor
Interferon Mediator
Antiviral
Other Bioactive Compounds from
Marine Sponges: Antimicrobial
Compound
Discodermins B, C, D
TopsentiasterolSulfates
Arenosclerins A, B , C
Axinellamines B-D
Acanthosterol I and J
Oceanapiside
Spongistatin
Leucascandrolide A
Class
Cyclic Peptide
Sulfated Sterol
Alkylpiperidine
Imidazo-azolo-imidazole alkaloid
Sulfated Sterol
Biasminohydroxylipid
Glycoside
Polyether Macrolide
Lactone
Oxazole-Containing
Polyether Macrolide
Activity
Antibacterial
Antibacterial/Antifungal
Antibacterial
Antibacterial
Antifungal
Antifungal
Antifungal
Antifungal
Other Bioactive Compounds from
Marine Sponges: “Antifouling”
Compound
Kalihinene X
Kalihipyran B
10 b -Formarnidokalihinol
Pseudoeratidine 2
Ceratinamide A and B
C22 Ceramide
Formoside
Axynyssimides
Class
Isocyanoterpenoid
Isocyanoterpenoid
Isocyanoterpenoid
Dibromopyrrole-Containing
Spermidine Derivative
Bromotyrosine Derivative
Ceramide
Triterpene Glycoside,
Sterol Diperoxide
Sesquiterpene Carbonimide
Dichlorides
Other Bioactive Compounds from
Marine Sponges: Anticancer
Compound
BRS1
Isoaaptamine
Debromohymenialdisine
Adociasulfates
Laulimalide
Peloruside A
Hemiasterlin
Dictyostatin
Spongistatin 1
Halichondrin B
Arenastatin A
Latrunculin A
Neoamphimedine
Elenic Acid
Agelasphin
Class
Diamino-dihydroxypolyunsaturated lipid
Benzonaphthyridine alkaloid
Pyrrole-Guanidine Alkaloid
Activity
Protein Kinase C Inhibitor
Triterpenoid Hydroquinone
Macrocyclic Lactone
Macrocyclic Lactone
Tripeptide
Macrocyclic Lactone
Bis{spiroacetal} Macrolide
Polyether Macrolide
Macrocyclic Lactan/Lactone
Thiazole Macrolide
Pyridoacridine Alkaloid
Kinesin Inhibitor
Stabilization of Microtubules
Stabilization of Microtubules
Stabilization of Microtubules
Stabilization of Microtubules
Tubulin Polymerization Inhib.
Tubulin Polymerization Inhib.
Tubulin Polymerization Inhib.
Actin-Depolymerization
Topoisomerase II Inhibitor
Alkylphenol
a-Galactosylceramide
Topoisomerase II Inhibitor
NKT Cell Activator
Protein Kinase C Inhibitor
Protein Kinase C Inhibitor
Other Bioactive Compounds from
Marine Sponges: Antiinflammatory
Compound
Manoalide
Dysidotronic Acid
Ircinin-1 and -2
Petrosaspongiolides
Spongidines A-d
Topsentin
Scalaradial
Cacospongionolide B
Jaspaquinol
Subersic Acid
Class
Cyclohexane
Sesterterpenoid
Drimane
Sesquiterpenoid
Acyclic Sesterterpenoid
Cheilantane
Pyridinium Alkaloid
Bis-Indole Alkaloid
Scalarane Sesterterpene
Sesterterpene Lactone
Diterpene Benzenoid
Diterpene Benzenoid
Mode of Action
Phospholipase A2 Inhibitor
Phospholipase A2 Inhibitor
Phospholipase A2 Inhbitor
Phospholipase A2 Inhibitor
Phospholipase A2 Inhibitor
Phospholipase A2 Inhibitor
Phospholipase A2 Inhibitor
Phospholipase A2 Inhibitor
Lipoxygenase Inhibitor
Lipoxygenase Inhibitor
Discovery of Manoalide
Luffariella variabilis
HO
O
O
Manoalide
O
HO
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
Phospholipids in Cell Membrane
Phospholipids
R2
O
H2C
O
R1
O
CH
O
H2C
O
O
P
O
X
O-
R2
O
H2C
O
O
CH
O
Arachidonate
O
H2C
O
P
O-
O
X
Phospholipase-A2 (PLA2) Hydrolyzes
Phospholids at sn-2 Position
R2
O
H2C
O
O
CH
O
O
H2C
O
P
O
X
O-
PLA2
R2
O
H2C
O
COOH
HO
CH
O
H2C
O
Arachidonic Acid
P
O
X
O-
Lysophospholipid
Catalytic Mechanism of PLA2
Free Arachidonic Acid is Substrate for
Eicosanoid Pathway
Arachidonic Acid
COOH
Cyclooxygenases-1 and -2
(COX-1 and -2)
Lipoxygenases (LOX)
O
OH
COOH
COOH
HO
OH
OH
OH
Prostagalandin A2 (e.g.)
Leukotriene B4 (e.g.)
COO-
HO
O
OH
Thromboxane B2 (e.g.)
Eicosanoid Release Triggers
Inflammation Response
Inflammation Response in Wound
Healing
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
Bee Venom Assay for PLA2 Activity
3H-Labeled
Dipalmitoyl Phosphatidyl Choline
O
3
H
O
3H
CH2
3H
3H
3H
O
CH
CH3
3H
O
H2 C
N+
O
O
P
O
O-
PLA2 from Bee Venom
3
H
3
H
3
H
OH
3H-Labeled
Palmitic Acid
Radioassay
O
CH3
CH3
Manoalide Inhibits PLA2 Activity of
Bee Venom
Reynolds et al. (1991) J. Biol. Chem., 266: 16512-7
Manoalide Irreversibly Inhibits PLA2
R2
O
H2C
O
O
CH
O
O
H2C
O
P
O
X
O-
PLA2
R2
O
H2C
O
COOH
HO
CH
O
H2C
O
Arachidonic Acid
P
O
X
O-
Lysophospholipid
Ring-Opening of Manoalide Creates
Binding Sites
HO
O
O
O
HO
OH
O
HO
O
O
CH
CH
Michael
Addition
OH
O
HO
OH
O
CH
CH
O
Schiff’s Base
O
O
O
OH
Amide
Manoalide Binds Lysine Residues in PLA2
HO
O
O
O
HO
HO
O
O
CH
OH
N
Lys
OH
O
CH
CH
N
N
Lys
Lys
OH
Commerical Potential of Manoalide

Licensed by Allergan® Pharmaceuticals

Phase-I Clinical Trials for Treatment of Psoriasis

Commercially Available Probe for PLA2
Drugs from the Sea: Cnidaria
Phylum Cnidaria
Class Anthozoa
“Sea Pens”
“Corals”
“Sea Fans”
Coral Biology
 Corals are FOUNDATION of reefs
Zooxanthellae
= Symbiotic algae in coral
Planula
Coral Diseases
“Bleaching”
“Tolerant”
Susceptible
Microbial Infection
Bioactive
Compounds
Bioactive Compounds from Cnidarians:
Pseudopterosin
PsA
PsB
PsC
PsD
Pseudopterogorgia
elisabethae
(“Purple Sea Whip”)
O
R1O
OH
R1=R2=R3=H
R1=Ac, R2=R3=H
R2=Ac, R1=R3=H
R3=Ac, R1=R2=H
O
OR3
R2O
Look, Fenical, Jacobs and Clardy (1986) Proc. Natl. Acad. Sci., 83: 6238-40
Pseudopterosin A Inhibits Inflammation
Response in Mouse Model
O
HO
OH
O
OH
HO
Pseudopterosin A
Look, Fenical, Jacobs and Clardy (1986) Proc. Natl. Acad. Sci., 83: 6238-40
Pseudopterosin A and E (PsA and PsE):
Antiinflammatory Mechanism(s)
O
HO
OH
OH
O
OH
O
HO
OH
Pseudopterosin A
OH
O
Pseudopterosin E
Mayer et al. (1998) Life Sci., 62: 401-407
OH
PsA and PsE Inhibit Mouse Ear Edema
Mayer et al. (1998) Life Sci., 62: 401-407
PsA and PsE Inhibit PBQ- and ZymosanInduced Writhing
Mayer et al. (1998) Life Sci., 62: 401-407
PsE Inhibits Zymosan-Induced Peritoneal
Prostaglandin and Leukotriene Exudate
Mayer et al. (1998) Life Sci., 62: 401-407
PsA and PsE Inhibit Zymosan-Induced
Release of Prostaglandin and
Leukotriene from Murine Peritoneal
Macrophages
Mayer et al. (1998) Life Sci., 62: 401-407
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 AntiInflammatory for Dermatitis


Cosmetic Ingredient
Pseudopterosins
PsA
PsB
PsC
PsD
O
R1O
R1=R2=R3=H
R1=Ac, R2=R3=H
R2=Ac, R1=R3=H
R3=Ac, R1=R2=H
Seco-PsA
Seco-PsB
Seco-PsC
Seco-PsD
O
O
R1O
OR3
R2O
OH
OH
OH
PsF
R1=R2=R3=H
R1=Ac, R2=R3=H
R2=Ac, R1=R3=H
R3=Ac, R1=R2=H
O
OR3
R2O
OH
O
PsY
OH
O
Seco-PsJ
O
O
O
HO
O
HO
HO
HO
HO
OH
HO
OH
OH
Terpenoid Biosynthesis
ATP
OH
ADP ATP
ADP
O
OH
O
COO-
COO-
HO
-O
P
Mevalonate
O
P
O-
O
O-
5-Phosphomevalonate
“Isoprene”
O
-O
P
O-
O
O
P
O
+
O
O-
H
O
P
O-
P
O
O-
Isopentyl Diphosphate
-O
-O
O
O
O-
Dimethylallyl Diphosphate
O
O
P
P
O-
O
Geranyl Diphosphate
Terpenoid Biosynthesis
O
-O
P
O-
O
O
P
O-
O
Geranyl Diphosphate
OH
Limonene Menthol
Monoterpenoids
(C-10)
Terpenoid Biosynthesis
O
-O
P
O-
O
O
O
P
O-
+
O
-O
P
O-
H
O
O
P
O-
Isopentyl Diphosphate
(IPP)
Farnesyl Diphosphate
O
-O
P
O-
O
O
P
O-
O
O
Geranyl Diphosphate
Terpenoid Biosynthesis
O
-O
P
O-
O
O
O
P
+
O
O-
-O
P
O
O
O-
H
P
O-
O
Geranyl Diphosphate
Isopentyl Diphosphate
(IPP)
Farnesyl Diphosphate
O
O
“Steroids”
(C-30)
-O
P
O
P
O
O-
O-
Triterpenoids
(C-30)
Zingiberene
Squalene
Sesquiterpenoids
(C-15)
HO
Lanosterol
Terpenoid Biosynthesis
O
-O
P
O
O
O
P
O-
+
O
O-
-O
P
O-
H
O
O
P
O-
O
Geranyl Diphosphate
Isopentyl Diphosphate
(IPP)
Farnesyl Diphosphate
O
-O
P
O-
O
-O
P
O-
O
O
P
O-
O
O
O
P
O-
O
+ IPP
Terpenoid Biosynthesis
O
-O
P
O
O
O
P
O-
+
O
O-
-O
P
O-
H
O
O
P
O-
O
Geranyl Diphosphate
Isopentyl Diphosphate
(IPP)
Farnesyl Diphosphate
O
-O
P
O-
O
-O
P
O-
O
O
P
O-
O
+ IPP
O
O
P
O
O-
Diterpenoids
(C-20)
(-)-Kaurene
Terpenoid Biosynthesis
O
-O
P
O
O
O
P
O-
+
O
O-
-O
P
O-
H
O
O
P
O
Geranyl Diphosphate
O-
Isopentyl Diphosphate
(IPP)
Farnesyl Diphosphate
O
-O
P
O-
O
-O
P
O-
O
O
P
O-
O
+ IPP
O
O
P
O
O-
+ IPP
O
-O
P
O-
O
O
P
O
O-
Sesterterpenoids (C-25)
Manoalide is a Sesterterpene
HO
O
O
O
HO
Biosynthesis of
Pseudopterosins
Elisabethatriene
H
Erogorgiaene
H
H
OPP
GGPP
H
H
H
H
OH
OH
OH
HO
OH
OH
O
O
O
HO
HO
O
HO
OH
OH