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Bioactive Compounds from Marine “Plants and Microorganisms”
Bioactive Compounds from Vascular Plants
Bioactive Compounds from Algae (Part 1)
Macroalgae
Microalgae (Part 1)
Five Kingdoms of Biological Diversity
Monera(“Prokaryotes”)
Protista
Animalia
FungiPlantae
Five Kingdoms of Biological Diversity
Monera(“Prokaryotes”)
Animalia
FungiPlantae
Protista
Plant Kingdom: Transition to Land
“Bryophytes”
“Ferns” and Relatives
Gymnosperms(Conifers and Cycads)
Angiospermsa.k.a. Magnoliophyta(“Flowering Plants”)
Lilliopsida(monocotyledons)
Magnoliopsida(dicotyledons)
Vascular Plants
Seed Plants
Aquatic Plants
Division Magnoliophyta Class Lilliopsida
Order AlismatalesFamily AlismataceaeFamily AponogetonaceaeFamily AraceaeFamily ButomaceaeFamily CymodoceaceaeFamily HydrocharitaceaeFamily JuncaginaceaeFamily LimnocharitaceaeFamily PosidoniaceaeFamily PotamogetonaceaeFamily RuppiaceaeFamily ScheuchzeriaceaeFamily TofieldiaceaeFamily Zosteraceae
Order Alismatales
Aquatic Plants
Division Magnoliophyta Class Lilliopsida
Order AlismatalesFamily AlismataceaeFamily AponogetonaceaeFamily AraceaeFamily ButomaceaeFamily CymodoceaceaeFamily HydrocharitaceaeFamily JuncaginaceaeFamily LimnocharitaceaeFamily PosidoniaceaeFamily PotamogetonaceaeFamily RuppiaceaeFamily ScheuchzeriaceaeFamily TofieldiaceaeFamily Zosteraceae
“Seagrass”
“Seagrasses”
Seagrass Distribution
Bioactive Compounds from Seagrasses: Antiinflammatory
Constituents from Zostera japonica
Hexane Fraction (H5) from Z. japonica Inhibits Release of Tumor Necrosis Factor (TNF)and Interleukin (IL)
TNF IL-1
Bioactive Compounds from Seagrasses: Antiinflammatory
Constituents from Zostera japonica
Fatty Acids are the Major Constituents of Fraction H5
“Mangroves”16 Plant Families
Major Components:Acanthacaeae - e.g. Avicennia spp. (“Black Mangrove”)Combretaceae - e.g. Laguncularia spp. (“White Mangrove”)Rhizophoraceae - e.g. Rhizophora spp. (“Red Mangrove”)
Bioactive Compounds from Mangroves: Antiinflammatory Compounds from Rhizophora
mangle (Red Mangrove)
Low Molecular Weight Polyphenols Extracted from R. mangle Inhibit COX-2 and PLA2
Bioactive Compounds from Marine “Plants and Microorganisms”
Bioactive Compounds from Vascular Plants
Bioactive Compounds from Algae (Part 1)
Macroalgae
Microalgae (Part 1)
What Are Algae?
Monera(“Prokaryotes”)
Protista
Animalia
FungiPlantae
What Are Algae?
Monera(“Prokaryotes”)
Animalia
FungiPlantae
Protista
“Algae”
Eukaryotic Kingdom Protista
Dinophyta (“Dinoflagellates”)Raphidophyta (“Raphidophytes”)Bacillariophyta (“Diatoms”)Chrysophyta (“Golden Algae”)Chlorophyta (“Green Algae”)Phaeophyta (“Brown Algae”)Rhodophyta (“Red Algae”)
Prokaryotic Kingdom Monera (Bacteria)
Cyanobacteria (“Blue-Green Algae”)
“Macroalgae”
“Microalgae”
What Are Algae?
Pigments and Algae
PBs4
Chl a1 b c d Car. 2 Xanth.3 PC5 PE6
Cyanobacteria x x x
Dinoflagellata x x x xBacillariophyta x x x xChrysophyta x x x xChlorophyta x x xPhaeophyta x x x xRhodophyta x x x x
1Chl = Chlorophyll; 2Car. = Carotenoids; 3Xanth. = Xanthophylls; 4PB = Phycobilins (Phycobiloproteins); 5PC =
Phyocyanin; 6PE = Phycoerythrin
Macroalgae
Chlorophyta(“Green Algae”)
Phaeophyta(“Brown Algae”)
Rhodophyta(“Red Algae”)
Bioactive Compounds from Chlorophyta:
Capisterones A and B
O
O
H
H
H
OR OSO3-
A R = AcB R = H
Capisterones A (1) and B (2) Reverse Fluconazole-Resistance
Xing-Cong et al. (2005) J. Nat. Prod., 69: 542-6
Yeast Transformed with MDR1 and CDR1
MDR1/CDR1 Gene Product is ATP-Binding Cassette
(ABC) Protein
MDR1/CDR1 P-Glycoproten Pumps Drugs
and Toxins out of Cell
Capisterones A (1) and B (2) Reverse Fluconazole-Resistance
Xing-Cong et al. (2005) J. Nat. Prod., 69: 542-6
Algicidal Polyunsaturated Fatty Acids (PUFAs) from Ulva
fasciatus
O
OH
O
OH
O
OH
Hexadeca-4,7,10,13-Tetraenoic Acid (HDTA)
Octadeca-6,9,12,15-Tetraenoic Acid (ODTA)
-Linolenic Acid
Bioactive Compounds from Phaeophyta: Phloroglucinols
from Ecklonia cava
8,8’-Bieckol 8,4”-Dieckol
O
O
HO OH
OH
HO
OH
OH
O
O
OHO
OH
OH
OH
HO
O
O
O
O
HO OH
OH
HO
OH
OH
O
O
O
OHHO
OH
OH
OH
HO
O
Phloroglucinol Tannins(“Phlorotannins”)
OH
HO OH
Phloroglucinol
O
O
HO OH
OH
HO
OH
OH
O
O
OHO
OH
OH
OH
HO
O
O
Phlorotannins from Ecklonia cava Inhibit HIV Reverse-Transcriptase (RT) and
Protease
IC50 (M)RT Protease
Eckol >100 >1008,8’-Bieckol 0.51 81.58,4”-Dieckol 5.31 36.9Phlorofucofureckol A >100 >100
Nevirapine 0.28 Not TestedAcetyl Pepstatin Not Tested 0.34
Taken from Ahn et al. (2004) Biol. Pharm. Bull., 27: 544-7
Bioactive Compounds from Phaeophyta: Diterpenes from
Dictyota
OHC
OR
H
OHC
R (6R)-6-Hydroxydichotoma-3,14-Diene-1,17-Dial (Da-1) -H(6R)-6-Acetoxydichotoma-3,14-Diene-1,17-Dial (AcDa-1) -Ac
(from D. meunstralis)
Da-1 and AcDa-1 Inhibit HIV-1 Replication by Inhibition of
Reverse Transcriptase
Bioactive Compounds from Rhodophyta: Antiviral Activity
of Carrageenan
H
O
OSO3-
H
O
H
H
OHHO
OH
O
H
H
H
O
H
O
OH
H
HO
OH
H
O
H
H
OSO3-HO
OH
O
H
CH2OSO3-
H
H
O
H
OH
OSO3-
H
-carrageenan
-carrageenan
-carrageenan
HO
OSO3-
H
O
H
H
OHHO
OH
O
H
H
H
O
H
O
OSO3-
H
n
n
n
Carrageenan Strongly Human Papilloma Virus (HPV)
Psuedovirus (PsV)
Carrageenan Resembles Sulfated Glycosaminoglycans
HeparanSulfate
HPV Attaches to Host Cells by Binding Heparan Sulfate Bound
to Cell Membrane
Carrageenan Binds HPV Capsids
Carrageenan is Found ALREADY in Number of Contraceptives
Buck et al. (2006)
Eukaryotic Microalgae
Dinoflagellata
RaphidophytaBacillariophyta
(“Diatoms”)
“Harmful Algal Blooms” (HABs)
HAB Toxins Typically Associated with Human Health Effects
“Amnesic Shellfish Poisoning” (ASP)“Paralytic Shellfish Poisoning” (PSP)
“Neurotoxic Shellfish Poisoning” (NSP)“Ciguatera Fish Poisoning” (CFP)
“Diarrhetic Shellfish Poisoning” (DSP)
NH
CH2COOH
CH3
H
COOH
COOH
H3C
Domoic AcidPseudonitzschia spp.
“Amnesic Shellfish Poisoning” (ASP)
Domoic Acid Binds to Kainate-Type Glutamate Receptors
Kainate Receptor is “Non-NMDA” Kainate Receptor is “Non-NMDA” Glutamate ReceptorGlutamate Receptor
Glu
Glu
Ca2+
1. Free-Radicals (e.g. Nitric Oxide, Reactive Oxygen Species)2. Damage to Membranes (e.g. Collapse of Mitochondria)3. Loss of ATP4. Apoptosis/Necrosis5. Excitatory Neurotransmitters
Kainate Receptor is “Non-NMDA” Kainate Receptor is “Non-NMDA” Glutamate ReceptorGlutamate Receptor
Domoic Acid Causes Lesion in the Hippocampus
N
NH
HN
+H2N
R1
R4
NH2+
OH
OH
R2 R3
H
Saxitoxin (STX), Gonyautoxins (GTX) and
Other “PSP Toxins”
“Paralytic Shellfish Poisoning” (PSP)R4:
R1 R2 R3 H H H STX GTX5H H OSO3- GTX2 C1H OSO3- H GTX3 C2OH H H NeoSTX GTX6OH H OSO3- GTX1 C3OH OSO3- H GTX4 C4
e.g. Alexandrium tamarense
O
O
NH2 O
O
NHSO3
STX Binds Voltage-Gated Sodium Channels at the Same Site as TTX
= STX or TTX
Minor Modification of Sodium Channel Leads to Resistance to STX in Shellfish
Reduced Toxicity Leads to Increased Accumulation of STX in Shellfish
Higher Mortality for STX-Exposed Clams (black) vs. Unexposed (white)
Higher Accumulation in Resistant (black) vs. Sensitive (white) Clams
“Florida Red Tide”
Karenia brevis
“Florida Red Tide”
O
O
O
O
O
O
O
O
O
OO
CH2
OHC
HO
CH3
CH3
CH3
CH3
CH3
CH3
O
O
O
O
O
O
9O
OO
OO
O
CH2
HO
H3C
CH3
H 3C
H3C
O
H
Brevetoxin A (PbTx-1)
Brevetoxin B (PbTx-2)
Brevetoxins (PbTx): The Florida Red Tide Toxin
O
O
O
O
O
O
O
O
O
OO
CH2
OHC
HO
CH3
CH3
CH3
CH3
CH3
CH3
O
O
O
O
O
O
9O
OO
OO
O
CH2
HO
H3C
CH3
H 3C
H3C
O
H
PbTx-1PbTx-2
Brevetoxins (PbTx) from Marine Raphidophytes
Chattonella antiquaHeterosigma akashiwo
Fibrocapsa japonica
PbTx is Voltage-Gated Sodium Channel Activator
= PbTx= STX/TTX
Activation/Inactivation of Voltage-Gated Sodium Channels
LePage et al. (2003) Brain Res., 959:120-7.
PbTx is Leads to Sustained Excitation of Neurons
Other PbTx Toxicoses?
PbTx and Heart Rate
PbTx Inhibits Pulmonary Resistance in Sheep Model
O
O
O
O
O
HOH
HH
H
H
H
O
OH
H
H
H
Brevenal (from K. brevis)
Drugs from “Red Tide?”
Brevenal is Natural Antagonist of PbTx Bronchoconstriction and
Pulmonary Resistance
Bronchoconstriction Tracheal Mucus Velocity (TMV)
O
O O
O
O
O
9
O
O
O
O
O
O
OHCH3
CH3
H
HH
H
HHO
HH
HHHH
H
OH
H H
HH
H
H
HH
H
H
H 3C
OH
H3C
OH
HO
Ciguatoxin (CTX)
Gambierdiscus toxicus
“Ciguatera”
“Ciguatera”Maitotoxin
…and others?
CTX is Voltage-Gated Sodium Channel Activator
…and Binds Channel at Same Location as PbTx
= PbTx
= CTX
= STX/TTX
“Ciguatera” Fish Poisoning (CFP)
Predatory Reef Fish are Primary Vectors
“Diarrhetic Shellfish Poisoning” (DSP)
O
O
O
O
O O
O
O
O
CH3CH 3
H3C
OH
OH
O
CH3O
H 3C
OH
OH
H3C
Pectenotoxin-1 (PTX-1)
Dinophysis spp.
CH3
H
R4
O
O O
O
O O
O
O
CH3
CH3
H
R2OH
OH
H
OR3
H3C OH
R1
R1 R2 R3 R4OA CH3 H H HDTX-1 CH3 CH3 H HDTX-2 H CH3 H HDTX-3 CH3 CH3 Acyl HAcanthafolicin CH3 H H H 9,10-episulfide
Okadaic Acid and Related Dinophysistoxins (DTXs) and Acanthafolicin are Ser/Thr
Phosphatase Inhibitors
Prorocentrum spp. Dinophysis spp.
Drugs from Dinoflagellate Algae?
OH
O
OCH3
HO
HO
HO
CH3
CH3
O
H3C
e.g. Amphidinolide A
Amphidinolides (and Related Compounds) Inhibit Cancer Cells
Cytotoxicity IC50 (g/mL)L1210 KB
Amphidinolide A 2.0 5.7Amphidinolide B 0.00014 0.0042Amphidinolide C 0.0058 0.0046Amphidinolide D 0.019 0.08Amphidinolide E 2.0 10Amphidinolide F 1.5 3.2Amphidinolide G 0.0054 0.0059Amphidinolide H 0.00048 0.00052
Taken from Kobayashi and Ishibashi (1993) Chem. Rev., 1753-69.
Drugs from Dinoflagellate Algae?
Zooxanthellotoxins are Vasoconstrictors
Symbiodinium spp.(=Symbiotic Zooxanthellae)
Polyketides from Dinoflagellates
“Polyether Ladders”
Macrolides Linear Polyethers
O
O
O
O
O
O
O
O
O
OO
CH2
OHC
HO
CH3
CH3
CH3
CH3
CH3
CH3
O
e.g. PbTx-1
O
O
O
O
O O
O
O
O
CH3CH 3
H3C
OH
OH
O
CH3O
H 3C
OH
OH
H3C
e.g. PTX-1
CH3
H
R4
O
O O
O
O O
O
O
CH3
CH3
H
R2OH
OH
H
OR3
H3C OH
R1
e.g. Okadaic Acid
E
Sc
O
R
Sa
O
COOH
E
Sc
Sa
O
H
O
RE
Sc
Sa
O
H
OH
RE
Sc
Sa
O
H
R
E
Sc
Sa
O
H
R
-ketoacyl synthase (KS)
-ketoacyl reductase (KR)
Dehydrase (DH)
Enoyl reductase (ER)
Polyketide Synthases (PKSs) are Modular Enzymes
CO2
NADPH NADP+
H2O
Are PKSs of Dinoflagellate or Bacterial Origin?
Taken from Snyder et al. (2005) Phytochemistry, 66: 1767-80.
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