Alkaloids

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Around 12,000 alkaloids of various types have been known to occur in all land plants, including more than 150 families. The important families are Apocynaceae, Papaveraceae, Fabaceae, Ranunculaceae, Rubiaceae, Rutaceae, Solanaceae, and less common lower plants and fungi (ergot alkaloids). In plants, alkaloids generally exist as salts of organic acids like acetic, oxalic, citric, malic, lactic, tartaric, tannic and other acids. Some weak basic alkaloids (such as nicotine) occur freely in nature. A few alkaloids also occur as glycosides of sugar such as glucose, rhamnose and galactose, e.g. alkaloids of the solanum group (solanine), as amides (piperine), and as esters (atropine, cocaine) of organic acids [4, 38].

In plants, alkaloids may be present systematically in whole plants, or they may be accumulated in large amounts in specific organs like roots (aconite, belladonna), stem bark (cinchona, pomegranate) and seeds (nux vomica, Areca). In angiosperms, alkaloids are more common in dicots than in monocots.

Alkaloids have known to humans for several centuries. They are a diverse group of low-molecular-weight, nitrogen-containing compounds found in about 20% of plant species (Fig. 2.2). Morphine, an alkaloid from latex of the opium poppy, was isolated by F.W. Serturner in 1806, whose structure could be confirmed in 1952 due to the stereochemical complexity of the molecule [39]. Later on, other alkali-like active principles were isolated and identified, e.g. narcotine in 1817 by Robiquet, emetine in 1817 by Pelletier and Magendie, and so on. The term 'alkaloid' was coined by W. Meibner, a German pharmacist, meaning 'alkali like'. Later it was demonstrated that the alkalinity was due to the presence of a basic nitrogen atom. The first alkaloid synthesized was coniine in 1886 by Ladenburg, which had already been isolated in 1827 [4].

According to Pelletier [40] "an alkaloid is a cyclic organic compound containing nitrogen in a negative oxidation state which is of limited distribution among living organisms". Sometimes it is not possible to draw a clear line between true alkaloids and certain plant bases. Simple bases, such as methylamine, trimethylamine and other straight-chain alkylamines, are not considered alkaloids. Other compounds such as betaines, choline and muscarine (present in fig agaric, Amanita muscarea) are also excluded from alkaloids by some experts. These compounds are synthesized from amino acids and categorized as biological amines or protoalkaloids because their nitrogen is not involved in a heterocycle system. Similarly, polyamines (pu-trescine, spermine, spermidine) are also excluded. Some authorities even exclude the phenylalkylamines, such as P-phenylethylamine (mistletoe, Viscum album; barley, Hordeum vulgare), dopamine (banana, Musa sapientum), ephedrine (Ma huang, Ephedra sinica), mescaline (peyote, Lophora williamsii) and tryptamine (Acacia species). Widely distributed vitamin B1 (thiamine) is not categorized as an alkaloid even though it contains a nitrogen in heterocycle and has physiological activity. Similarly, purine-based compounds (caffeine, theophilline, theobromine) are also excluded by some workers, as they are not derived from amino acids [4]. However, a neutral compound such as colchicine from autumn crocus (Colchicum autumnale), in which the nitrogen is present in an amide group, is an alkaloid because of other traits like medicinal properties and restricted distribution in plants. Other examples of neutral compounds such as alkaloids are piperine from black pepper (Piper ni-grum), indicine-n-oxide (Heliotropium indicum), di-n-oxide trilupine (Lupinus bar-biger, L. laxus), betaines e.g. stachydrine (Medicago sativa) and trigonelline (in fenugreek, garden peas, oats, potatoes, coffee, hemp) [4].

The potent physiological activity of many alkaloids has also led to their use as pharmaceuticals, stimulants, narcotics and poisons. Alkaloids currently in clinical use include the analgesics morphine and codeine, the anticancer agent vinblastine, the gout suppressant colchicine, the muscle relaxant (+) tubocurarine, the antiar-rythemic ajmalicine, the antibiotic sanguinarine and the sedative scopolamine. The plant alkaloids like caffeine in tea and coffee and nicotine in all preparations (smoking, chewing) of tobacco are widely consumed daily [4].

Piperidine alkaloids such as coniceine, coniine and N-methyl coniine are present in Conium maculatum. Apart from tobacco alkaloids, nicotinic acid and its derivatives are a major pyridine alkaloid present in plants. The most commonly occurring

morphine O

camptothecin n/

camptothecin n/

atropine atropine

vinblastine Fig. 2.2 Alkaloids

apomorphine

exatecan exatecan

tritopium

co2ch3

vinflunine

OH fV

'OAc co2ch3

galanthamine

galanthamine caffeine

cocaine

Fig. 2.2 (continued)

cocaine

Fig. 2.2 (continued)

compound is trigonelline (N-methyl-nicotinic acid), which is present in Trigonella foenum-graecum. Anticholinergic alkaloids hyoscyamine, atropine and hyoscine (scopolamine) are found principally in plants of the family Solanaceae. Datura species contain more than 30 alkaloids. D. stramonium and D. innoxia are the main sources of hyoscyamine and scopolamine respectively. Other species known to contain tropane alkaloids are Atropa belladonna (Deadly nightshade), Hyoscya-mus niger (Henbane), H. muticus, Dubosia hybrids, D. myoporoides and D. leich-hardtii [41]. Nicotine and tropane alkaloids are formed in the roots and transported to the aerial parts of the plant [42]. The tropane alkaloids possess an 8-azabicyclo octane nucleus and are found in plants of three families, Solanaceae, Erythroxy-laceae and Convolvulaceae.The attractive berries of these plants contain these alkaloids, which are toxic. Fewer than three berries of Henbane (Hyoscyamus niger) or deadly nightshade (Atropa belladonna), both of which contain scopolamine and hyoscyamine, can cause death in infants. Both the tropane ring moiety of the tropane alkaloids and the pyrrolidine ring of nicotine are derived from putrescine by way of N-methyl putrescine (Fig. 2.3). Because putrescine is metabolized to polyamines such as spermidiene and spermine, the N-methylation of putrescine catalysed by putrescine N-methyltransferase is the first committed step in the biosynthesis of these alkaloids [43, 44].

Galanthamine hydrobromide is an Amaryllidaceae alkaloid obtained from Galan-thus and Crinum species that has been used traditionally in Russia, Bulgaria and Turkey for neurological conditions. It is currently obtained by synthesis and used as an acetyl cholinesterase inhibitor in the treatment of Alzheimer's disease [45].

Cocaine in Coca (Erythroxylum coca) was the first local anaesthetic to be discovered. Leaves of a few species of Erythroxylum, indigenous to Peru and Bolivia,

N-methyl putrescine

4-Aminobutanol

Nicotinic acid i

1-Methy|-A' pyrrolium^Tropinone cation

Nicotine

1-Methy|-A' pyrrolium^Tropinone cation

TR-I

Tropine

TR-I

Tropine

Cocaine D - . Hyoscyamine Pseudotropine

Phenylalanine

Phenyllactic acid i il

6ß-Hydroxy-Calystegin hyoscyamine

Scopolamine

Fig. 2.3 Biosynthesis of tropane alkaloids from N-methyl putrescine contain 0.6 to 1.8% cocaine. The leaves of the plant have been used for centuries by natives to increase endurance and to promote a sense of well-being. Cocaine was isolated in 1859 by A. Niemann for its central-nervous-system-stimulating activity, which can lead to dependence liability; cocaine has been a drug of abuse. These alkaloids are synthesized from tropic acid. Outside the Solanaceae, tropane alkaloids occur in two other plant families. Within the Erythroxylaceae, the genus Erythrox-ylon comprises about 200 widely distributed, tropical species found mainly in S. America and Madagascar. E. coca is the only plant currently cultivated for cocaine production.

About 2500 benzyl isoquinoline alkaloids have been isolated from diverse taxa, including well-established drugs like morphine, sanguinarine, berberine and pal-matine. The biosynthesis of these alkaloids begins with the conversion of tyrosine into dopamine and 4-hydroxyacetaldehyde [39]. Isoquinoline-type alkaloids show strong pharmacological activities like those of morphinan-, protoberberine-and benzophenenthridine-type alkaloids, and they are widely distributed in the plant kingdom, mainly in Papaveraceae, Berbidaceae, Ranunculaceae and Menisperma-ceae.

The opium poppy (Papaver somniferum) is one of the oldest cultivated plants. The therapeutic use of latex obtained from unripe capsules of poppy was recorded by Theophrastus in the third century BCE. Dioscorides (100 CE) described the curative properties of the opium poppy and presented the different uses for both latex and extracts of whole plants. Laticifers are found associated with the vascular bundle in plant parts. The morphinan alkaloids, morphine, codeine and thebaine, are found both in roots and in aerial plant parts and specifically accumulate in vesicles within laticifers. Details of opium alkaloid biosynthesis, the enzymes involved and localization are given elsewhere [39], [46-48]. These alkaloids are used in modern medicine for the treatment of pain, cough and diarrhoea. Two new semisynthetic derivatives of age-old drugs, morphine and atropine, have been developed and are being used clinically for Parkinson's disease and for chronic obstructive pulmonary disease, respectively. Apomorphine hydrochloride [49] is a dopamine receptor agonist, while triotropium bromide is derived from atropine [50].

The antimalarial activity of the alkaloid quinine obtained from the bark of Cinchona species (C ledgeriana, C. pubescens and C. officinalis) has been known for many centuries. Besides their pharmaceutical use, Cinchona alkaloids are also used in the food and soft drink industry because of their bitter taste [4].

Terpenoid indole alkaloids comprise a group of about 3000 compounds with well-known compounds such as antineoplastic agents vinblastine and camptothecin, the antimalarial drug quinine and the rat poison strychinine. Terpenoid indole alkaloids consist of an indole component provided by tryptamine and a terpenoid moiety derived from secologanin. Tryptophan, a shikimic acid biosynthetic pathway product, is converted to tryptamine by tryptophan decarboxylase (TDC). The biosynthesis of these alkaloids is discussed elsewhere in detail [39, 42], [51-53]. New derivatives of vinblastine and camptothecin are currently in clinical trials for their anticancer properties, such as vinflunine and exatecan, respectively [2]. Besides vincristine and vinblastine, Catharanthus roseus is famous for its more than 100 secologanin-derived monoterpene indole alkaloids (MIAs). The monomeric MIA aj-malicine is used in the treatment of circulatory disorders, whereas the heterodimeric MIAs vinblastine and vincristine are powerful antitumour drugs [54].

Purine alkaloids are widely distributed within the plant kingdom (Fig. 2.2) and have been detected in at least 90 species belonging to 30 genera. Caffeine and thre-obromine, methylated derivatives of xanthine, are generally the main purine alkaloids and are regularly accompanied in low concentrations by the two methylxan-thines theophylline and paraxanthine, as well as by methylated uric acids such as theacrine, methylliberine and liberine. Purine alkaloids, being present in tea and coffee, are widely consumed in the human diet across the continents. Plant species from different families are made into a pleasant stimulant, e.g. coffee (Coffea arabica, C. robusta), tea (Camellia sinenesis), cocoa (Theobroma cacao), mate (Ilex pguariensis) and cola (Cola nitida) [55].

2.6.2 Phenolics

Simple phenolics are termed compounds and have at least one hydroxyl group attached to an aromatic ring, e.g. catechol. Most compounds having a C6C1 carbon skeleton, usually with a carbonyl group attached to the aromatic ring, are phenolic compounds [56].

Simple phenylpropanoids are defined as secondary metabolites derived from phenylalanine, having a C6C3 carbon skeleton, and most of them are phenolic acids, e.g. cinnamic acid, o-coumaric acid, p-coumaric acid, caffeic acid and fer-ulic acid [57]. A simple phenylpropanoid can conjugate with an intermediate from the shikimic acid pathway, such as quinic acid, to form compounds like chlorogenic acid. Phenolic compounds having a C6C3C6 carbon skeleton include flavonoids (including anthocyanins) and isoflavonoids.

Phenolic compounds are generally synthesized via the shikimate pathway (Fig. 2.4), but the polyketide pathway can also provide some phenolics, such as orcinols and quinones. Phenolic compounds derived from both pathways are quite common, e.g. flavonoids, stilbenes, pyrones and xanthones [58].

The shikimate pathway, a major biosynthetic route for both primary and secondary metabolism, starts with phosphoenol pyruvate and erythrose-4-phosphate and ends with chorismate [59]. Chorismate is an important branching point since it is the substrate for all subsequent products (Fig. 2.4) [60]. A great diversity of phenolic compounds are synthesized through these intermediate products, e.g. phenylalanine is a common precursor for C6C3 and C6C3C6 compounds, and their polymers such as tannins and lignins [38].

Resveratrol (3, 5, 4'-trihydroxystilbene) is an oligomeric polyphenol found as dimer, trimer and tetramer in the families Vitaceae, Dipterocarpaceae, Cyperaceae, Gnetaceae and Leguminosae. Resveratrol is synthesized from phenylalanine, mediated by the enzyme stilbenes synthase, while chalcone synthase converts pheny-lalanine into flavonoids. Resveratrol is implicated in the prevention of cancer and

Shikimic acid-

Chlorogenic acid

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