F. Strychnine
Biological Sources It is abundantly found in the seeds of Strychnos Nux Vomica L. (Loganiaceae) (Nux Vomica, Strychnine); beans of Strychnos ignatti Berg. (Loganiaceae); roots of S. cinnamomifolia Thw.; seeds, bark and wood of S. colubrina Linn.; and plant of S. malaccensis Benth. (Syn: S. gautheriana Pierre).
Chemical Structure
Strychnidine-10-one; (C21H22N2O2)
Salient Features
1. Strychnine contains two N-atoms even then it happens to be a mono-acidic base.
2. Strychnine readily forms a variety of salts, such as: nitrate, N6-oxide, phosphate and sulphate. Interestingly, the N-atom which is specifically involved in the salt formation is the one that is located farthest from the aromatic benzene ring.
3. The second N-atom is strategically positioned as an amide nitrogen; and, therefore, it does not exhibit any basic characteristics.
Isolation Strychnine may be isolated from the seeds of S. nux vomica by adopting the following steps sequentially:
1. The seeds of nux vomica are dried, ground and sieved which are mixed with an adequate quantum of pure slaked lime and made into a paste by adding a requisite amount of water. The wet mass thus obtained is dried at 100°C and extracted with hot chloroform in a continuous extractor till the extraction is completed.
2. The alkaloids are subsequently removed from the chloroform solution by shaking with successive portions of dilute sulphuric acid (2N). The combined acid extracts are filtered to get rid of any foreign particles or residue.
3. To the resulting acidic filtrate added an excess of ammonia to precipitate the alkaloids (strychnine + brucine).
4. The precipitate is extracted with ethanol (25% v/v) several times which exclusively solubilizes brucine, and ultimately leaves strychnine as an insoluble residue.
5. The residue containing strychnine is filtered off and is finally purified by repeated recrystallization from ethanol.
Characteristic Features
1. It is obtained as brilliant, colourless cubes from a mixture of chloroform and ether having mp 275-285°C, and d18 1.359.
2. Its specific optical rotation [α]18D-104.3° (C = 0.254 in ethanol); [α]25D-13° (C = 0.4 in chloroform).
3. Its dissociation constant pKa (25°) 8.26.
4. It has uvmax (95% ethanol); 2550, 2800, 2900 Å (E1% 1cm 377, 130, 101).
5. Solubility Profile: 1g dissolves in 182 ml ethanol, 6.5 ml chloroform, 150 ml benzene, 250 ml methanol, 83 ml pyridine; and very slightly soluble in water and ether.
6. A solution of strychnine containing 1 part in 700,000 parts of water gives a distinct bitter taste.
Identification Tests Strychnine may be identified either by specific colour tests or by specific derivatives:
(a) Colour Tests
1. Sulphuric Acid-Dichromate Test: Strychnine (5-10 mg) when dissolved in a few drops of concentrated sulphuric acid and stirred with a crystal of pure potassium dichromate [K2Cr2O7] it gives an instant reddish-violet to purple colouration.
Note: Strychnine derivatives will also give this test except strychnine nitrate.
2. Mandelin’s Reagent Test: Strychnine or its corresponding salt when treated with Mandelin’s Reagent* it gives rise to a violet to blue colouration.
3. Ammonium Vanadate (V) Test: Strychnine or its salt when treated with a saturated solution of ammonium vanadate, it produces a violet to blue colouration.
4. Nitric Acid Test: Strychnine on being treated with a trace of HNO3 (conc.) yields an instant yellow colouration.
Note: A similar test with Brucine gives an intense orange-red colouration. It may be used to differentiate between strychnine and brucine.
(b) Strychnine Derivatives: The various important strychnine derivatives are as given under:
1. Strychnine Nitrate (C21H23N3O5): It is obtained as colourless, odourless needles or while crystalline powder 1g dissolves in 42 ml water, 10 ml boiling water, 150 ml ethanol, 80 ml ethanol at 60°C, 105 ml chloroform, 50 ml glycerol; and insoluble in ether. It shows a pH ~ 5.7.
2. Strychnine N6– Oxide (C21H22N2O3): It is obtained as monoclinic prisms from water which decompose at 207°C. It has pK value 5.17. It is found to be freely soluble in ethanol, glacial acetic acid, chloroform; fairly soluble in water; sparingly soluble in benzene; and practically insoluble in ether and petroleum ether.
3. Strychnine Phosphate (C21H25N2O6P): It is usually obtained as its dihydrate salt (2O6P.2H2O) which is colourless or while crystals or white powder. 1g dissolves in slowly in ~ 30 ml water, more soluble in hot water, and slightly soluble in ethanol. The aqueous solution is acidic to litmus.
4. Strychnine Sulphate (C42H46N4O8S): It normally crystallizes as pentahydrate [2C21H22N2O2.H2SO4.5H2O]. It is colourless, odourless, very bitter crystals or white crystalline powder. It effloresces in dry air and loses all its water of crystallization at 100°C. It shows mp when anhydrous ~ 200°C with decomposition. 1g dissolves in 35 ml water, 7 ml boiling water, 81 ml ethanol, 26 ml ethanol at 60°C, 220 ml chloroform, 6 ml glycerol, and insoluble in ether. A 1 : 100 solution shows pH 5.5.
5. Strychnine Gluconate Pentahydrate (C27H34N2O9.5H2O): Its crystals darken above 80°C. It is soluble in 2 parts water ~ 40 parts ethanol. The aqueous solution is found to be neutral.
6. Strychnine Glycerophosphate Hexahydrate (C45H53N4O10P.6H2O): 1g dissolves in ~ 350 ml water, ~ 310 ml ethanol; slightly soluble in chloroform; and very slightly soluble in ether.
7. Strychnine Hydrochloride Dihydrate (C21H23ClN2O2.2H2O): It is obtained as trimetric prisms which are efflorescent in nature. 1g dissolves in ~ 40 ml water, ~ 80 ml ethanol, and insoluble in ether. The pH of a 0.01 M solution is 5.4.
Uses
1. Strychinine is extremely interesting pharmacologically and is regarded as a valuable tool in both physiologic and neuroanatomic research.
2. It is extremely toxic, and functioning as a central stimulant.
3. It causes excitation of all parts of the central nervous system and blocks inhibitory spinal inpulses at the post synaptic level. This may lead to an exaggeration in reflexes ultimately leading to tonic convulsions.
4. The drug is rarely used in modern medical practice but is utilized as a vermin killer i.e., animal or insect killer.
5. It is used chiefly in poison baits for rodents.
Biosynthesis of Yohimbine, Reserpine, Rescinnamine, Vinblastine, Vincristine and Strychnine Dehydogeissoschizine (keto-form) undergoes isomerization by means of the nucleophilic attack on to carbonyl through a conjugated system, which subsequently forms an onium ion that upon reduction produces yohimbine as shown below:
Reserpine and deserpidine are essentially the trimethoxybenzoyl esters of yohimbine-type alkaloids; whereas, rescinnamine is a trimethoxycinnamoyl ester. Interestingly, both reserpine and rescinnamine contain an additional methoxyl moiety present strategically on the indole ring system at C-11, which is accomplished by virtue of hydroxylation and methylation at a late stage along the pathway. A predominant and characteristic feature of these alkaloids is that they exhibit the opposite stereochemistry at C-3 to yohimbine and strictosidine as depicted below:
The biosynthetic pathway leading to vinblastine and vincristine is supposedly involve the following vital steps:
1. An oxidative reaction on catharanthine, catalysed by an enzyme peroxidase, thereby producing a peroxide that aptly loses the peroxide as a leaving group, ultimately breaking a carbon-carbon covalent bond as shown in the diagram given below.
2. The intermediate electrophilic ion is attacked on to the conjugated iminium system by the vindoline, whereby C-5 of the indole nucleus being appropriately activated by the –OCH3 moiety located at C-6, and also by the N-atom present in the indole ring.
3. The resulting adduct is subsequently reduced in the dihydropyridinium ring by NADH*-dependent 1, 4-addition thereby giving rise to the substrate for hydroxylation.
4. Ultimately, reduction of the above resulting product generates vinblastine.
5. The oxidized product from vinblastine, with its N-formyl moiety rather than N-methyl on the vindoline fragment, may finally yield vincristine.
The biosynthetic pathway leading to strychnine essentially comprise of the following steps, namely:
1. Preakuammicine loses one C-atom via hydrolysis followed by decarboxylation.
2. Addition of the two extra C-atoms is accomplished by means of Aldol-condensation reaction with acetyl-CoA, whereby it yields the Wieland-Gumlich aldehyde as a complexed hemiacetal form.
3. The subsequent construction of ether and amide linkages gives rise to the formation of stryctinine from the above hemiacetal as shown below.
--------------------------------------------------
* NADH = Nicotinamide adenine dinucleotide (reduced form).
