Coumarin Bitter Principles

2.4 Coumarin Bitter Principles
Coumarin nucleous is generated by the combination of benzene and á-pyrone as already mentioned under section 2.3. A good number of coumarin bitterprinciples have been isolated and characterized for their efficacious medicinal values, such as: psoralen, methoxsalen, bergapten, imperatorin, angelicin and pimpinellin. Out of these the first four drugs have already been discussed under the chapter on ‘Phenylpropanoids’ under Sections 2.3.3.1 through 2.3.3.4. The remaining two drugs shall now be described in the sections that follow:
2.4.1 Angelicin
Biological Sources It occurs in the fruit or root of Angelica archangelica L. (A. officinalis Moench) (Umbelliferae) (Angelica; Garden Angelica; European Angelica).
Chemical Structure

Angelicin
It is an angular furocoumarin.
Uses Angelica is useful for dyspepsia, enteritis, flatulance, gastritis, insomnia, neuralgia, rheumatism and ulcers.
2.4.2 Pimpinellin
Biological Sources It occurs in the fruits and rhizomes of Pimpinellin saxifraga L., Heracleum spondylium L.; H. lanatum Michx; and H. panaces belonging to the natural order Umbelliferae.
Chemical Structure

Pimpinellin
5, 6-Dimethoxy-2H-furo [2, 3-h]-1-benzopyran-2-one; (C13H10O5)
Isolation Pimpinellin may be isolated by the methods suggested by Fujita and Furuya*, and by Svendsen et al.**
Characteristic Features
1. It is obtained as off-white needles from methylene chloride/hexane having mp 119°C.
2. It is found to be practically insoluble in water; and soluble in ethanol.
3. It also undergoes isomerism to give rise to isopimpinellin as shown below:

 isopimpinellin
Biosynthesis of Psoralen, Methoxsalen (Xanthotoxin), Bergapten, Angelicin and
Isopimpinellin The various steps that are involved in the biosynthesis of psoralen, xanthotoxin,bergapten, angelicin and isopimpinellin are given below in a sequential manner:
1. Umbelliferone is first produced by the interaction of an isoprene unit with an appropriate alkylating agent e.g., dimethylallyldiphosphate (DMAPP). Thus, the aromatic ring in the former gets duly activated at positions ortho to the hydroxyl group present in it.
2. The newly introduced dimethylallyl function present in demethyl-suberosin gets subsequently cyclized, having the phenolic moiety intact, to yield marmesin. However, this specific biotransformation is found to be catalyzed by a cytochrome P-450-dependent mono-oxygenase and also essentially requires cofactors such as NADPH and molecular oxygen.
3. It has been suggested appropriately that a second cytochrome P-450 dependent mono-oxygenase enzyme then cleaves off the hydroxyisopropyl portion (as a mole of acetone) from marmesin, thus producing the linear furocoumarin psoralen.
4. Psoralen is supposed to act as a precursor for the production of the subsequent series of further substituted furocoumarins, namely: bergapten, xanthotoxin, and isopimpinellin as shown below. Interestingly, such modifications are usually afforded due to steps taking place rather late in the biosynthetic pathway than occurring at the cinnamic-acid stage.
5. Angelicin—the so called angular furocoumarins, is the outcome of an identical sequence of reactions; however, these steps specifically involve dimethylallylation due to DMAPP at the alternative position ortho to the phenol.
Biosynthesis of Psoralen, Methoxsalen, Bergapten, Angelicin and Isoimpinellin
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* Fujita, Furuya, J. Pharm. Soc. Japan, 74, 795 (1954); 76, 535 (1956).
** Sevendsen et al. Planta Med., 7, 113 (1959).

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