Khellin and Cromoglicate

The dried ripe fruits of Ammi visnaga (Umbelliferae/Apiaceae) have a long history of use in the Middle East as an antispasmodic and for the treatment of angina pectoris. The drug contains small amounts of coumarin derivatives, e.g. visnadin (Figure 3.40) (compare Ammi majus, a rich source of furocoumarins, page 146), but the major constituents (2-4%) are

OMe O R = H, khellol R = Glc, khellol glucoside

visnadin

cromoglicate (cromoglycate)

nedocromil

nedocromil

2Na furochromones, including khellin and visnagin (Figure 3.34), and khellol and khellol glucoside (Figure 3.40). Both khellin and visnadin are coronary vasodilators and spasmolytic agents, with visnadin actually being the more potent agent. Khellin has been used in the treatment of angina pectoris and bronchial asthma. The synthetic analogue cromoglicate (cromoglycate) (Figure 3.40) is a most effective and widely used agent for the treatment and prophylaxis of asthma, hay fever, and allergic rhinitis. Cromoglicate contains two chromone systems containing polar carboxylic acid functions, joined by a glycerol linker. The mode of action is not fully established. It was believed to prevent the release of bronchospasm mediators by stabilizing mast cell membranes, but an alternative suggestion is that it may act by inhibiting the effect of sensory nerve activation, thus interfering with bronchoconstriction. It is poorly absorbed orally and is thus administered as inhalation or nasal spray. Eyedrops for relief of allergic conjunctivitis are also available. The more potent nedocromil (Figure 3.40) has also been introduced.

ring originate by metabolism of a five-carbon dimethylallyl substituent attached to C-6 (for a full discussion, see furocoumarins, page 145). The 8-methoxy group in khellin is absent from visnagin, so must be introduced late in the sequence. The key intermediate is thus 5,7-dihydroxy-2-methylchromone. On inspection, this has the alternate acetate-derived oxygenation pattern and a methyl chain starter, so is formed from a poly-^-keto chain through Claisen condensation then heterocyclic ring formation by an overall dehydration reaction. After formation of the furan ring via the C-dimethylallyl derivative peucenin and then visamminol, visnagin can be obtained by O-methylation. Alternatively, further hydroxylation para to the free phenol, followed by two methylations, yields khellin. The antiasthmatic properties of khellin have been exploited by developing the more polar, water-soluble derivative cromoglicate*.

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