Gambierol is a marine polycyclic ether toxin which is produced by the dinoflagellate Gambierdiscus toxicus. Gambierol is collected from the sea at the Rangiroa Peninsula in French Polynesia. The toxins are accumulated in fish through the food chain and can therefore cause human intoxication. The symptoms of the toxicity resemble those of ciguatoxins, which are extremely potent neurotoxins that bind to voltage-sensitive sodium channels and alter their function. These ciguatoxins cause ciguatera 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, composed of eight ether rings, 18 stereocenters, 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 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 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 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. 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 and Stille coupling of compound 8 with dienyl stannane (compound 9) provide gambierol.
Mechanism of action
Gambierol acts as a low-efficacy partial agonist at voltage-gated sodium channels (VGSC’s) and as a high affinity inhibitor of voltage-gated potassium currents. It reduces the current through potassium channels irreversibly by stabilizing some of the closed channels. It acts as an intermembrane anchor where it displaces lipids 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 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 of the membrane potential. The K1.3 channel however, has additional functions by regulating the Ca2+ signaling for T cells. If they are blocked, the T cells at the site of inflammation paralyse and are not reactivated. K3.1 channels are responsible for the high frequency firing of action potentials. If the K channels are closed, the depolarized membrane cannot repolarize to its resting state, causing a permanent action potential. This leads to paralysis of, for example, the respiratory system and therefore suffocation of the organism.
In neurons, gambierol has been reported to induce Ca oscillations because of blockage of the voltage-gated potassium channels. The Ca oscillations involve glutamate 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 stimulates MAPKs to phosphorylate ERK1/2 which induce outgrowth of neurites. This is however dependent on intracellular concentrations and interaction of the NMDAR receptors They both work bidirectionally.