Gambierol is a marine polycyclic
ether
In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again be c ...
toxin which is produced by the
dinoflagellate
The dinoflagellates (Greek δῖνος ''dinos'' "whirling" and Latin ''flagellum'' "whip, scourge") are a monophyletic group of single-celled eukaryotes constituting the phylum Dinoflagellata and are usually considered algae. Dinoflagellates are ...
''
Gambierdiscus toxicus
''Gambierdiscus toxicus'' is a species of photosynthetic unicellular eukaryote belonging to the Alveolata, part of the SAR supergroup. It is a dinoflagellate which can cause the foodborne illness ciguatera, and is known to produce several natur ...
''.
Gambierol is collected from the sea at the Rangiroa Peninsula in
French Polynesia
)Territorial motto: ( en, "Great Tahiti of the Golden Haze")
, anthem =
, song_type = Regional anthem
, song = " Ia Ora 'O Tahiti Nui"
, image_map = French Polynesia on the globe (French Polynesia centered).svg
, map_alt = Location of Frenc ...
. The toxins are accumulated in fish through the
food chain
A food chain is a linear network of links in a food web starting from producer organisms (such as grass or algae which produce their own food via photosynthesis) and ending at an apex predator species (like grizzly bears or killer whales), det ...
and can therefore cause human
intoxication
Intoxication — or poisoning, especially by an alcoholic or narcotic substance — may refer to:
* Substance intoxication:
** Alcohol intoxication
** LSD intoxication
** Toxidrome
** Tobacco intoxication
** Cannabis intoxication
** Cocaine i ...
. The symptoms of the toxicity resemble those of
ciguatoxins
300px, Chemical structure of the ciguatoxin CTX1B
Ciguatoxins are a class of toxic polycyclic polyethers found in fish that cause ciguatera.
There are several different chemicals in this class. "CTX" is often used as an abbreviation.
* - C ...
, which are extremely potent
neurotoxins
Neurotoxins are toxins that are destructive to nerve tissue (causing neurotoxicity). Neurotoxins are an extensive class of exogenous chemical neurological insultsSpencer 2000 that can adversely affect function in both developing and mature nerv ...
that bind to voltage-sensitive
sodium channels
Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the chann ...
and alter their function. These ciguatoxins cause
ciguatera
Ciguatera fish poisoning (CFP), also known simply as ciguatera, is a foodborne illness caused by eating reef fish whose flesh is contaminated with certain toxins. Such individual fish are said to be ciguatoxic. Symptoms may include diarrhea, vomi ...
fish poisoning. Because of the resemblance, there is a possibility that gambierol is also responsible for ciguatera fish poisoning. Because the natural source of gambierol is limited, biological studies are hampered. Therefore, chemical synthesis is required.
Structure and reactivity
Gambierol is a ladder-shaped
polyether
In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again be c ...
, composed of eight ether rings, 18
stereocenter
In stereochemistry, a stereocenter of a molecule is an atom (center), axis or plane that is the focus of stereoisomerism; that is, when having at least three different groups bound to the stereocenter, interchanging any two different groups c ...
s, and two challenging pyranyl rings having methyl groups that are in a 1,3-diaxial orientation to one another.
Different structural analogues were synthesized to determine which groups and side chains attached to the gambierol are essential for its toxicity. Not only the fused polycyclic ether core is essential, but also the
triene
In organic chemistry, polyenes are poly- unsaturated, organic compounds that contain at least three alternating double () and single () carbon–carbon bonds. These carbon–carbon double bonds interact in a process known as conjugation, result ...
side chain at C51 and the C48-C49 double bond were indispensable. In the triene side chain, the double bond between C57 and C58 was essential. The C1 and C8 hydroxy groups were not essential, but they enhance the activity. The conjugate diene in the triene side chain also enhances the toxicity.
Synthesis
The
synthesis
Synthesis or synthesize may refer to:
Science Chemistry and biochemistry
*Chemical synthesis, the execution of chemical reactions to form a more complex molecule from chemical precursors
** Organic synthesis, the chemical synthesis of organ ...
of gambierol consists of two tetracyclic precursor molecules, one alcohol and one acetic acid, that fuse together. The whole synthesis of gambierol is depicted in the figure below. After obtaining the octacyclic backbone, the tail is added via
Stille coupling
The Stille reaction is a chemical reaction widely used in organic synthesis. The reaction involves the coupling of two organic groups, one of which is carried as an organotin compound (also known as organostannanes). A variety of organic electroph ...
. The acetic acid (compound 1) and alcohol (compound 2) are converted to compound 3. The reaction of compound 3 with the titanium alkylidene from dibromide 1,1-dibromoethane, provides cyclic enol ether (compound 4). Oxidation of the alcohols gives majorly compound 5, but also compound 6. These are both ketones, but they have other
stereochemistry
Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereois ...
. Compound 6 can be converted back in compound 5 with reactant c, thereby moving the equilibrium towards compound 5. This ketone can be converted further to produce reactive gambierol. By reductive cyclization of the D ring, the octacyclic core structure (compound 7) was made. Oxidation of compound 7 to the aldehyde was followed by formation of the diiodolefin. Stereoselective reduction, global
deprotection
A protecting group or protective group is introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction. It plays an important role in multistep organic synthesis.
In man ...
and Stille coupling of compound 8 with dienyl stannane (compound 9) provide gambierol.
Mechanism of action
Gambierol acts as a low-efficacy partial
agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
at
voltage-gated sodium channels
Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the channel ...
(VGSC’s) and as a high affinity inhibitor of voltage-gated potassium
currents
Currents, Current or The Current may refer to:
Science and technology
* Current (fluid), the flow of a liquid or a gas
** Air current, a flow of air
** Ocean current, a current in the ocean
*** Rip current, a kind of water current
** Current (stre ...
.
It reduces the current through
potassium channels
Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of cel ...
irreversibly by stabilizing some of the closed channels.
It acts as an intermembrane anchor where it displaces
lipids
Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...
and prohibits the voltage sensor domain of the channel from moving during physiologically important changes. This causes the channel to remain in the closed state and lowers the current.
Gambierol also decreases the
amplitude
The amplitude of a periodic variable is a measure of its change in a single period (such as time or spatial period). The amplitude of a non-periodic signal is its magnitude compared with a reference value. There are various definitions of amplit ...
of inward sodium currents and
hyperpolarizes the inward sodium current activation.
Gambierol has a high affinity for especially
K1.1-
1.5 channels and the
K3.1 channel. K1.1-1.5 channels are responsible for
repolarization
In neuroscience, repolarization refers to the change in membrane potential that returns it to a negative value just after the depolarization phase of an action potential which has changed the membrane potential to a positive value. The repolarizat ...
of the
membrane potential
Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. That is, there is a difference in the energy required for electric charges ...
. The
K1.3 channel however, has additional functions by regulating the
Ca2+ signaling for
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
s. If they are blocked, the T cells at the site of
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
paralyse
Paralysis (also known as plegia) is a loss of motor function in one or more muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory damage. In the United States, roughly 1 in 5 ...
and are not reactivated.
K3.1 channels are responsible for the high
frequency
Frequency is the number of occurrences of a repeating event per unit of time. It is also occasionally referred to as ''temporal frequency'' for clarity, and is distinct from ''angular frequency''. Frequency is measured in hertz (Hz) which is eq ...
firing of
action potential
An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...
s.
If the K channels are closed, the
depolarized membrane
A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. B ...
cannot repolarize to its resting state, causing a permanent action potential. This leads to paralysis of, for example, the
respiratory system
The respiratory system (also respiratory apparatus, ventilatory system) is a biological system consisting of specific organs and structures used for gas exchange in animals and plants. The anatomy and physiology that make this happen varies grea ...
and therefore
suffocation of the organism.
In
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s, gambierol has been reported to induce Ca
oscillation
Oscillation is the repetitive or periodic variation, typically in time, of some measure about a central value (often a point of equilibrium) or between two or more different states. Familiar examples of oscillation include a swinging pendulum ...
s because of blockage of the voltage-gated potassium channels. The Ca oscillations involve
glutamate
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
release and activation of
NMDARs (glutamate receptors). This is however secondary to the blockade of potassium channels.
The oscillations reduce the cytoplasmic Ca
threshold for the activation of
Ras
Ras or RAS may refer to:
Arts and media
* RAS Records Real Authentic Sound, a reggae record label
* Rundfunk Anstalt Südtirol, a south Tyrolese public broadcasting service
* Rás 1, an Icelandic radio station
* Rás 2, an Icelandic radio stati ...
. Ras stimulates
MAPKs to
phosphorylate
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, ...
ERK1/2 which induce outgrowth of
neurite
A neurite or neuronal process refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture ...
s. This is however dependent on intracellular concentrations and interaction of the NMDAR receptors They both work bidirectionally.
An increase in intracellular calcium concentration also activates the
nitric oxide synthase
Nitric oxide synthases () (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and p ...
to produce
nitric oxide
Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...
.
In combination with a
superoxide
In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of the ...
, nitric oxide forms
peroxynitrite
Peroxynitrite (sometimes called peroxonitrite) is an ion with the formula ONOO−. It is a structural isomer of nitrate,
Preparation
Peroxynitrite can be prepared by the reaction of superoxide with nitric oxide:
:
It is prepared by the react ...
and causes
oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily Detoxification, detoxify the reactive intermediates or to repair the resulting damage. Disturbances ...
in different sorts of tissues. This explains the toxic symptoms derived from intake of gambierol.
Metabolism
Metabolism of gambierol is not known yet, but the expectation is that gambierol acts almost the same as the
ciguatoxin
image:ciguatoxin.svg, 300px, Chemical structure of the ciguatoxin CTX1B
Ciguatoxins are a class of toxic Polycyclic compound, polycyclic polyethers found in fish that cause ciguatera.
There are several different chemicals in this class. "CTX" ...
s. Ciguatoxins are polycyclic polyether compounds. Their molecular weight is between 1.023 and 1.159 Dalton. Gambierol is structurally similar to ciguatoxins and it can be synthesized together with them.
Excretion of these ciguatoxins is largely via the feces and in smaller amounts via urine.
The compounds are very
lipophilic
Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipop ...
and will therefore diffuse to multiple organs and tissues, for example the liver, fat and the brain. The highest concentration was found in the brain, but muscles contained the highest total amount after a few days. Because gambierol is lipophilic, it can easily persist and accumulate in the fish food chain. The
detoxification
Detoxification or detoxication (detox for short) is the physiological or medicinal removal of toxic substances from a living organism, including the human body, which is mainly carried out by the liver. Additionally, it can refer to the period of ...
pathways are still unknown, but it is possible to eliminate the gambierol. This will take several months or years.
Efficacy and side effects
The membrane potential and
calcium signaling
Calcium signaling is the use of calcium ions (Ca2+) to communicate and drive intracellular processes often as a step in signal transduction. Ca2+ is important for cellular signalling, for once it enters the cytosol of the cytoplasm it exerts allos ...
in
T lymphocytes
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell rec ...
are controlled by ion channels. T cells can be activated if membrane potential and calcium signaling are altered, because they are coupled to
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
pathways. If these signal transduction pathways are disrupted, it can prevent the T cells from responding to
antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
s. This is called
immune suppression
Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse react ...
. Gambierol is a potent blocker of
potassium channel
Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of cel ...
s, which for a part determine the membrane potential. Gambierol is therefore a good option for the development of a drug that can be used in
immunotherapy
Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...
. This is for example used in diseases like
multiple sclerosis
Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
,
diabetes mellitus type 1
Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar f ...
and
rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...
.
Treatment with gambierol is not being used yet, because the compound is toxic and also blocks other channels and thereby disrupts important processes. Intake of gambierol can also cause pain, because Kv1.1 and Kv1.4 channels are blocked and that increases the excitability of central circuits. It also causes illness for several weeks. This is explained by the fact that gambierol is very lipophilic. Lipophilic compounds have high affinity for the
lipid bilayer
The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...
of cell membranes. It is likely that gambierol remains in the cell membrane for days or a few weeks, which explains the long term illness associated with gambierol treatment. There are also other symptoms already explained by the mechanism of action of gambierol, for example difficulties with respiration and
hypotension
Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dias ...
.
Gambierol is also an interesting compound in research into treatments of pathologies like
Alzheimer’s disease
Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As t ...
, which are caused by increased expression of
β-amyloid
Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid precursor protein (APP), which is ...
and/or
tau
Tau (uppercase Τ, lowercase τ, or \boldsymbol\tau; el, ταυ ) is the 19th letter of the Greek alphabet, representing the voiceless dental or alveolar plosive . In the system of Greek numerals, it has a value of 300.
The name in English ...
hyperphosphorylation
Hyperphosphorylation occurs when a biochemical with multiple phosphorylation sites is fully saturated. Hyperphosphorylation is one of the signaling mechanisms used by the cell to regulate mitosis. When these mechanisms fail, developmental problems ...
. Increases in β-amyloid accumulation and/or tau phosphorylation affects neurons the most. The neurons will then be degenerated and therefore this process has effects on the nervous system. However, gambierol can reduce this overexpression of β-amyloid and/or tau hyperphosphorylation in vitro and in vivo.
Gambierols function in inducing outgrowth of
neurite
A neurite or neuronal process refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture ...
s in a bidirectional manner can potentially be used after neural injury. After for example a trauma or a
stroke
A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
, gambierol can be used to change the
structural plasticity of the brain.
The possibility of gambierol to cross the
blood–brain barrier
The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
is very important in this case.
Toxicity
Poisoning by gambierol is normally caused after eating contaminated fish. Gambierol exhibits potent toxicity against mice at 50-80 μg/kg by
intraperitoneal injection
Intraperitoneal injection or IP injection is the injection of a substance into the peritoneum (body cavity). It is more often applied to animals than to humans. In general, it is preferred when large amounts of blood replacement fluids are needed ...
or 150 μg/kg when consumed orally.
Symptoms resemble those of
ciguatera
Ciguatera fish poisoning (CFP), also known simply as ciguatera, is a foodborne illness caused by eating reef fish whose flesh is contaminated with certain toxins. Such individual fish are said to be ciguatoxic. Symptoms may include diarrhea, vomi ...
poisoning. The symptoms concerning the
gastrointestinal tract
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organ (biology), organs of the digestive syste ...
are:
* Abdominal pain
* Nausea
* Vomiting
* Diarrhea
* Painful defecation
The neurological symptoms include:
* Paradoxical temperature reversion; cold objects feel hot and vice versa.
* Dental pain; teeth feel loose.
First aid
Always contact a doctor. There is no
antidote
An antidote is a substance that can counteract a form of poisoning. The term ultimately derives from the Greek term φάρμακον ἀντίδοτον ''(pharmakon) antidoton'', "(medicine) given as a remedy". Antidotes for anticoagulants are s ...
available for gambierol poisoning.
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Neurotoxins
Polyether toxins
Ion channel toxins
Non-protein ion channel toxins
Potassium channel blockers
Heterocyclic compounds with 7 or more rings