Pyrrolizidine Alkaloids

2.6.3 Pyrrolizidine Alkaloids


The bicyclic pyrrolizidine nucleus is formed by the utilization of two moles of ornithine and this pathway is accomplished via the intermediate putrescine. However, it has been observed that the plant sources usually synthesizing the pyrrolizidine alkaloids seem to be devoid of the decarboxylase enzyme that helps in the transformation of ornithine into putrescine; in fact, ornithine is really incorporated by way of arginine.
In nature, the pyrrolizidine alkaloids have a relatively broad stretch of distribution, but are specifically present in certain genera of the Leguminosae/Fabaceae (e.g.Crotalaria); the Compositae/Asteraceae (e.g.Senecio); and the Boraginaceae (e.g.Heliotropium, Symphytum, and Cynoglossum). Broadly speaking the pyrrolizidine bases do not occur in their free form, but are mostly found as esters with rare mono-or di-basic acids, the necic acids.
The two important alkaloids of this category are, namely: Retronecine and Senecionine, which shall be discussed as under:

Biosynthesis of Hygrine, Cuscohygrine, Cocaine, Carbamoyl Ecgonine (Methyl-ecgonine) and Hyoscyamine
Biosynthesis of Hygrine, Cuscohygrine, Cocaine, Carbamoyl Ecgonine (Methyl-ecgonine) and Hyoscyamine

A. Retronecine 

The most common base portion of the pyrrolizidine alkaloids is retronecine.
The ‘Necine’ bases are 1-methylpyrrolizidines of different stereochemical configurations and degree of hydroxylation which invariably occur as esters in alkaloids of SenecioCrotalaria and a plethora of genera of the Boraginaceae as stated earlier.
Biological Source It is obtained from the herbs of Heliotropium europaeum L. (Boraginaceae) (Heliotrope, Turnsole).
Chemical Structure

Retronecine
(1R-trans)-2, 3, 5, 7, a-Tetrahydro-1-hydroxy-1 H-pyrrolizine-7-methanol; (C8H13NO2).
Characteristic Features
1. It is obtained as crystals from acetone having mp 119-120°C.
2. It has the specific optical rotation [α]D20  +4.950 (C = 0.58 in ethanol).
Identification Test It gives the racemic mixture i.e., (±) form as crystals from acetone having mp 130-131°C.
Uses
1. The plant is used for cancer and is popularly known as “Herbe Du Cancer” in Europe.
2. It is also used for snakebite and scorpion stings.

B. Senecionine

Synonym Aureine;
Biological Source The hepatotoxic alkaloid is obtained from the whole plant of Senecio vulgaris L. (Compositae); weed of Senecio aureus L. (Asteraceae) (Squaw Weed, Liferoot, Golden Groundsel); and preblooming plant of Tussilago farfara L. (Asteraceae) (Coltsfoot, Coughwort, Horse-Hoof).
Chemical Structure

Senecionine  Synonym Aureine
12-Hydroxysenecionan-11, 16-dione; (C18H25NO5): is described by Barger and Blackie (1936).*
Characteristic Features
1. It is obtained as plates having mp 236°C and a bitter taste.
2. Its specific optical rotation [α ]D25 -55.10 (C = 0.034 in chloroform).
3. It is practically insoluble in water; freely soluble in chloroform; and slightly soluble in ether and ethanol.
Uses
1. It is used as an excellent drug to control pulmonary hemorrhage.
2. It is also used to hasten labour and check the pains of parturition.
Biosynthesis of Retronecine and Senecionine It has been observed that the plants synthesizing the above mentioned pyrrolizidine alkaloids seem to be devoid of the decarboxylase enzyme transforming ornithine into putrescine; in fact, ornithine is actually incorporated by way of arginine.
The various steps involved essentially in the biosynthesis of retronecine and senecionine are summarized as below:
1. Two moles of putrescine are condensed in an NAD+-dependent oxidative deamination reaction to yield the corresponding imine, which is subsequently transformed into homospermidine by the aid of NADH reduction.
2. The genesis of the creation of the pyrrolizidine skeleton is on account of the homospermidine molecule by a sequential series of interactions, such as: oxidative deamination, imine formation, intramolecular Mannich reaction, that specifically exploits the enolate anion produced from the aldehyde.
3. The ‘pyrrolizidine skeleton’ thus provides a C4N unit from ornithine, together with an additional four C-atoms from the same amino acid precursor.
4. The senecionine is a diester of retronecine with senecic acid.
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* Barger, Blackie, J. Chem. Soc. 743 (1936)

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