Santonin is a drug which was widely used in the past as an anthelminthic. It is a terpenoid and an organic compound consisting of colorless flat prisms, turning slightly yellow from the action of light and soluble in alcohol, chloroform and boiling water. According to the US Pharmacopoeia, santonin occurs "in colorless, shining, flattened, prismatic crystals, odorless and nearly tasteless when first put in the mouth, but afterward developing a bitter taste; not altered by exposure to air, but turning yellow on exposure to light. Nearly insoluble in cold water; soluble in 40 parts of alcohol at 15 °C. (59 °F.), in 250 parts of boiling water, and in 8 parts of boiling alcohol; also soluble in 140 parts of ether, in 4 parts of chloroform, and in solutions of caustic alkalies. When heated to 170 °C. (338 °F.), santonin melts, and forms, if rapidly cooled, an amorphous mass, which instantly crystallizes on coming in contact with a minute quantity of one of its solvents. At a higher temperature, it sublimes partly unchanged, and, when ignited, it is consumed, leaving no residue. Santonin is neutral to litmus paper moistened with alcohol. Santonin yields, with an alcoholic solution of potassium hydroxide, a bright pinkish-red liquid, which gradually becomes colorless. From its solution in caustic alkalies, santonin is completely precipitated by supersaturation with an acid".
Isolation It is derived from santonica (the unexpanded flower-heads of Artemisia maritima var. stechmanniana). Others refer to A. cina or A. chamaemelifolia as being the derivative species. The determination of the structure of santonin was the subject of intense early work. The initial photoproduct obtained from santonin is lumisantonin. In this rearrangement, the C-3 carbonyl group moves to C-2, the C-4 methyl moves to C-1, and the C-10 carbon inverts.
Anthelminthic use Santonin paralyzes parasitic worms (helminths), allowing them to be passed out of the body. Santonin has the effect of paralyzing the anterior (front) end of the worm, while having a stimulant effect on the posterior end, depending on the concentration. Because of this, the worm cannot coordinate itself, and loses its ability to maintain its position in the host. By using a purgative, the worm can easily be passed out. Experiments in the 1880s showed that even after 40 hours, santonin had no lethal effect on roundworms using a saturated solution in dilute alkali. Santonin was formerly listed in U.S. and British pharmacopoeia, but it has fallen out of use with the development of safer ascaricides and is no longer registered as a drug in most countries.
Reactions and properties Santonin can be converted to santonic acid (C15H20O4) via based-catalyzed hydrolysis followed by a multistep rearrangement process. Santonin dissolves in alkalies with formation of salts of this carboxylic acid. Santonin, in acetic acid solution, when exposed to sunlight for about a month, is converted into (colorless) photosantonic acid (C15H22O5) which is generally regarded as less toxic. The ethyl ester of the latter is obtained when an alcoholic solution of santonin is exposed to sunlight (Sestini). A yellow coloration is developed upon exposure of santonin to light. Santonin is optically levorotatory.
Proposed biosynthesis
The full biosynthesis of α-santonin has not been elucidated but α-santonin bears much similarity to parthenolide. The proposed biosynthesis begins with the cyclization of farnesyl diphosphate (FPP) to (+)-germacrene A by a sesquiterpene synthase. (+)-germacrene A hydroxylase then hydroxylates the isopropenyl side chain. The oxidation of germacratrien-12-ol to germacratrien-12-oic acid via the intermediate germacratrien-12-al is done by NADP+-dependent dehydrogenase(s). Germacratrien-12-oic acid is then hydroxylated at C6 subsequently followed by lactonization forming (+)-costunolide. It was proposed that the methylene of (+)-costunolide is reduced before the second ring closure. The bicyclic decalin ring system is formed via the eudesmyl cation followed by hydroxylation at C1. Further oxidation at C3 forms the β-ketohydroxyl which upon elimination of H2O completes the proposed biosynthetic pathway of α-santonin.
Photochemistry
The chemistry of α-santonin upon exposure to sunlight has the distinction of being the first reported organic photochemical reaction. Trommsdorff reported in 1834 that crystals of α-santonin first turned yellow upon exposure to sunlight before "exploding". The product of this solid-phase reaction was identified by Matsuura in 1968 as the product of photorearrangement, followed by a lattice-controlled Diels–Alder reaction and [2+2]-photocycloaddition. On the other hand, exposure to light in the solution phase results in the formation of monomeric skeletal rearrangement products. The mechanism of the photodimerization has been investigated in detail.
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