Alkaloids Derived from Anthranilic Acid

2.2 Alkaloids Derived from Anthranilic Acid

Anthranilic acid is found to be a key intermediate in the biosynthesis of L-tryptophan. Therefore, it has been established that this biotransformation ultimately is solely responsible to the elaboration of the indole alkaloids. In the course of this conversion, the anthranilic acid residue is specifically decarboxylated, thus the C6N skeleton is further utilized. In general, there are several such instances wherein the anthranilic acid itself serves as an alkaloid precursor, by employing various means and processes that essentially retain the full skeleton and further exploit the carboxyl function legitimately.
Interestingly, in mammals, L-tryptophan gets degraded back to anthranilic acid. However, this particular route is of least importance in the plant kingdom.
The alkaloids derived from anthranilic acid may be classified into three major categories, namely:
(i) Quinazoline alkaloids,
(ii) Quinoline alkaloids, and
(iii) Acridine alkaloids.
The aforesaid categories of alkaloids shall be discussed in an elaborated fashion hereunder individually.

2.2.1 Quinazoline Alkaloids

Vasicine is a quinazoline alkaloid which will be described below.

A. Vasicine

Synonym Peganine
Biological Sources It is obtained from the leaves of Adhatoda vasica (L.) Nees (Acanthaceae) (Malabar Nut, Adotodai, Paveltia); and the seeds of Peganum harmala L. (Rutaceae) (Harmel, Syrian Rue, African Rue).
Chemical Structure

Vasicine
1, 2, 3, 9-Tetrahydropyrrolo [2, 1-b] quinazoline-3-ol; (C11H12N2O).
Isolation It is isolated from the leaves of Adhatoda vasica* and also from the seeds of Peganum harmala** by adopting the standard methods of isolation described earlier in this chapter.
Characteristic Features
dl-Form: 1. It is obtained as needles from ethanol having mp 210°C.
2. It sublimes on being subjected to high vacuum.
3. It is soluble in acetone, alcohol, chloroform; and slightly soluble in water, ether and
benzene.
l-Form: 1. It is obtained as needles from ethanol with mp 212°C.
2. Its specific rotation [α ]D14 -2540 (C = 2.4 in CHCl3); [α ]D14–14  62° (C = 2.4 in ethanol).
Note: In dilute HCl it is obtained as its dextrorotatory form.
Identification Tests
1. Hydrochloride dihydrate derivative is obtained as needles having mp 208°C (dry).
2. Hydroiodide dihydrate derivative is formed as needles with mp 195°C (dry).
3. Methiodide derivative is obtained as needles from methanol having mp 187°C.
4. Acetyl vasicine derivative (C11H11N2O COCH3) is formed as crystals having mp 123°C and bp0.01 230-240°C.
Uses
1. It is mostly used as an expectorant and bronchodilator.
2. It also shows oxytocic properties very similar to those exhibited by oxytocin and methyl ergometrine.
3. Vasicine also shows abortifacient action which is due to the release of prostaglandins.
Biosynthesis of Vasicine Various studies in Peganum harmala have evidently revealed vasicine (peganine) to be derived from the anthranilic acid, while the remaining portion of the structure comprising of a pyrrolidine ring provided by ornithine. The probable mechanism of vasicine skeleton may be explained by virtue of the nucleophilic attack from the N-atom present in anthranilate upon the pyrrolidinium cation, ultimately followed by amide formation. However, interestingly this pathway is not being adopted in Justicia adhatoda. Thus, a comparatively less predictable sequence from Nacetylanthranilic acid and aspartic acid is observed as shown below:

Biosynthesis of Vasicine
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* Sen, Ghosh, J. Indian Chem. Soe., 1, 315 (1924);
** Späth, Nikawitz, Ber. 67, 45, (1934);

B. Vasicinone

Biological Source The plant source remain the same as described under vasicine.
Chemical Structure

Vasicinone
1, 2, 3, 9-Tetrahydropyrrolo [2, 1-b] quinazoline-6-one-3 ol (C11H10N2O2).
Uses It is used mainly as an expectorant which action is solely due to stimulation of the bronchial glands.

2.2.2 Quinoline Alkaloids

In general, the alkaloids containing essentially the ‘quinoline’ nucleus include a series of alkaloids obtained exclusively from the cinchona bark, the major members of this particular group are, namely: quinine, quinidine, cinchonine and cinchonidine. Interestingly, more than twenty five alkaloids have been isolated and characterized either from the Yellow Cinchona i.e., Cinchona calisaya Wedd. and Cinchona ledgeriana Moens ex Trimen, or from the Red Cinchona i.e., Cinchona succirubra Pavon ex Klotzsch (Family: Rubiaceae). The aforesaid alkaloids are also found in their hybrids as well as in the Cuprea Bark obtained from Remijia pedunculata and Remijia purdieana belonging to the natural order Rubiaceae.
However, it has been revealed that an average commercial yield of the cinchona alkaloids in the dry bark materials from the said plant materials are as follows: quinine (5.7%); quinidine (0.1-0.3%); cinchonine and cinchonidine (0.2-0.4%). Nevertheless, the other closely related minor alkaloids are present in relatively smaller quantities.
Basic Structures of Cinchona Alkaloids The various quinoline alkaloids, which possess potent medicinal activities are, namely: quinine, quinidine, cinchonine, and cinchonidine. It is interesting to observe that these alkaloids not only have a closely related structure but also similar medicinal characteristics. These alkaloids possess the basic skeleton of 9’-rubanol that is derived from the parent compound known as ruban. Thus, ruban is obtained from the combination of two distinct heterocyclic nuclii, namely: (a) 4-methyl quinoline nucleus, and (b) quinuclidine nucleus. However, this particular nomenclature was suggested by Rabe so as to simplify the naming of such compounds and also to signify its origin from the natural order Rubiaceae.


Basic Structures of Cinchona Alkaloids The various quinoline alkaloids
Basic Structures of Cinchona Alkaloids
In this context, a few important drugs belonging to the quinoline alkaloids shall now be discussed in the sections that follows:

A. Quinine

Biological Sources It is obtained from the bark of Cinchona calisaya Wedd; Cinchona ledgeriana Moens ex Trimen; Cinchona officinalis Linn. f.; Cinchona robusta How; and Cinchona succirubra Pavon ex Klotzsch belonging to family Rubiaceae.
Chemical Structure


Quinine
(8α, 9R)-6’-Methoxycinchonan-9-ol, (C20H24N2O2).
Isolation The schematic method of isolation of the Cinchona Alkaloids in general and that of quinine in particular has been provided in the following Flow-chart in a sequential manner. Hence, this particular flow-chart also includes the method of isolation of other important members of this group i.e., quinidine, cinchonine and cinchonidine as given under.
Notes
1. Bisulphates of cinchona as alkaloids [B.H2SO4] are readily soluble in water.
2. Quinine sulphate [Br.H2SO4] is sparingly soluble in water [1:720].
3. Cinchonine is practically insoluble in ether.
4. Tartrates of Quinine and Cinchonidine are insoluble, whereas the tartrates of Cinchonine and Quinidine are soluble in water.
Characteristic Features
1. The orthorhombic needles obtained from absolute ethanol are triboluminescent and having mp 177°C (with some decomposition).
2. It sublimes in high vacuum at 170-180°C.
3. Its specific rotation is [α ]D15  -169o (C = 2 in 97% ethanol); α ]D17  -117o (C = 1.5 in chloroform); and [α ]D15  -285o (C = 0.4 M in 0.1 N H2SO4).
4. Its dissociation constant pK1 (18°) is 5.07 and pK2 9.7.
5. Neutral Salt of Quinine [(B)2.H2SO4.8H2O]: It is formed by neutralization from boiling water, which is sparingly soluble in water (viz., 1 in 720 at 25°C). The octahydrate neutral salts of quinine undergoes efflorescence on being exposed to air and gets converted to the corresponding dihydrate salt which is more stable.
6. Acid Sulphate of Quinine [(B).H2SO4.7H2O]: The quinine bisulphate is soluble in water (1 in 8.5 at 25°C) and in ethanol (1 in 18). The aqueous solution is acidic to litmus.
7. Tetrasulphate Salt of Quinine [(B)2.2H2SO4.7H2O]: The tetrasulphate salt of quinine is very soluble in water.

Schematic Method of Isolation of Cinchona Alkaloids
Identification Tests
1. Fluorescence Test: Quinine gives a distinct and strong blue fluorescence when treated with an oxygenated acid, such as: acetic acid, sulphuric acid. This test is very marked and pronounced even to a few mg concentration of quinine.
Note: The hydrochloride and hydroiodide salts of quinine do not respond to this fluorescence test.
2. Thalleioquin Test: Add to 2-3 ml of a weakly acidic solution of a quinine salt a few drops of bromine-water followed by 0.5 ml of strong ammonia solution, a distinct and characteristic emerald green colour is produced. The coloured product is termed as thalleioquin, the chemical composition of which is yet to be established. This test is so sensitive that quinine may be detected to a concentration as low as 0.005%.
Notes: Quinidine and cupreine (a Remijia alkaloid) give also a positive response to this test; but cinchoninine and cinchonidine give a negative test.
3. Erythroquinine Test (or Rosequin Test): Add to a solution of quinine in dilute acetic acid 1-2 drops of bromine water, a drop of a solution of potassium ferrocyanide [K4(FeCN)6] (10% w/v), and to it add a drop of strong ammonia solution, the solution turns red instantly. In case, it is shaken immediately with 1 ml of chloroform, the red colour is taken up by the chloroform layer.
4. Herpathite Test: To a boiling mixture containing 0.25 g of quinine in 7.5 ml glacial acetic acid, 3 ml ethanol (90% v/v), 5 drops of conc. sulphuric acid and add to it 3.5 ml of 1% iodine solution in ethanol, the appearance of crystals of iodosulphate of quinine (i.e., sulphate of iodo-quinine)-is known as Herpathite after the name of its discoverer. It has the chemical composition [(B4).3H2SO4.2HI.I4.3H2O] which separates out as crystals (on cooling), having a metallic lustre that appears dark green in reflected light and olive green in transmitted light.
Uses
1. It is used as a flavour in carbonated beverages.
2. It is widely used as an antimalarial agent in tropical countries.
3. It is employed as a skeletal muscle relaxant.
Biosynthesis of Quinine The various steps whereby Coryanthe-type indole alkaloids are converted to quinoline derivatives have not yet been elucidated and hence established. Therefore, only a partial biosynthetic pathway may be written for quinine as given under.

B. Cinchonine

Biological Source Cinchonine is obtained from a variety of cinchona bark, especially in the bark of Cinchona micrantha R. and P. belonging to family Rubiaceae.
Chemical Structure Please see structure under Section 7.2.2.2, (9S-Cinchonan-9-ol) (C19H22N2O).
Isolation It has already been described under quinine Section ‘A’ above.
Characteristic Features
1. Its prisms, needles are obtained from ether and ethanol having mp 265°C.
2. It begins to sublime at 220°C.
3. Its specific rotation is [α]D +229° (in ethanol).
4. One gramme of it dissolves in 60 ml ethanol, 25 ml boiling ethanol, 110 ml chloroform and 500ml ether. It is practically insoluble in water.
Identification Tests
1. Cinchonine dihydrochloride (C19H22N2O.HCl): It is white or faintly yellow crystals or crystalline powder. It is freely soluble in water and ethanol.


Biosynthesis of Quinine
2. Cinchonine hydrochloride dihydrate (C19H22N2O.HCl.2H2O): It is obtained as fine crystals having mp when anhydrous 215°C with decomposition. One g dissolves in 20 ml of water, 3.5ml of boiling water, 1.5 ml of ethanol, 20 ml of chloroform and slightly soluble in ether.
3. Cinchonine sulphate dihydrate [(C19H27N2O)2.H2SO4.2H2O)]: It occurs as lustrous, very brittle crystals having mp 198°C (when anhydrous). One g dissolves in 65 ml of water, 30 ml of hot water, 12.5 ml of ethanol, 7 ml of hot ethanol, 47 ml of chloroform and slightly soluble in ether.

2.2.3 Acridine Alkaloids

The origin of the acridine-ring-system is by virtue of an extension of the process that essentially involves the combination of anthranilic acid and acetate/malonate as shown in the following sequence of reactions; whereas, a rather more direct route to the above leads to the quinoline-ring-system discussed in Section 7.2.2.2 earlier.


acridine-ring-system
There are a few typical examples of the acridine alkaloids, such as: Rutacridone, Acronycine and Melicopicine.

A. Rutacridone

Biological Source The fresh and dried leaves of Ruta graveolens L. (Rutaceae) (Rue, Garden Rue, German Rue).
Chemical Structure


Rutacridone
Uses
1. In Chinese medicine rue is considered as an emmenagogue, hemostat, intestinal antispasmodic, sedative, uterine stimulant, vermifuge, rheumatism, cold and fever.
2. In Poland, it is used as an aphrodisiac and choleretic.
3. The herb is used medicinally as a bitters, an aromatic stimulant, ecbolic and in suppression of the menses.
The chemical structures of acronycine and melicopicine are given below:


acronycine and melicopicine
Biosynthesis of Rutacridone, Acronycine and Melicopicine The anthraniloyl-CoA is observed to act as a starter-unit for the extension of chain via one molecule of malonyl-CoA, and formation of amide ultimately generates the heterocyclic system, that would adopt finally the more stable 4-hydroxy-2-quinolone form as shown in the following sequence of reactions. Interestingly, the position C-3 is highly nucleophilic; and, therefore, is susceptible to alkylation, especially via dimethylallyl diphosphate in the instance of all the three alkaloids, namely: rutacridone, acronycine, and melicopicine. This seems to allow the formation of additional six-membered oxygen containing heterocyclic ring system (acronycine); and five-membered oxygen containing heterocyclic ring system (rutacridone).

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