Introduction to the Different Classes of Natural Products

Springob, Karin; Kutchan, Toni M.

doi:10.1007/978-0-387-85498-4_1

Karin Springob³ &
Toni M. Kutchan³

5873 Accesses
19 Citations
3 Altmetric

Abstract

Plants produce an enormous variety of natural products with highly diverse structures. These products are commonly termed “secondary metabolites” in contrast to the “primary metabolites” which are essential for plant growth and development. Secondary metabolites were formerly regarded as “waste products” without physiological function for the plant. With the emergence of the field of chemical ecology about 30 years ago, it became evident, however, that these natural products fulfill important functions in the interaction between plants and their biotic and abiotic environment. They can serve, for example, as defense compounds against herbivores and pathogens, as flower pigments that attract pollinators, or as hormones or signal molecules. In addition to their physiological function in plants, natural products also have a strong impact on human culture and have been used throughout human history as condiments, pigments, and pharmaceuticals.

This chapter provides an overview about the diversity of secondary metabolites in plants, their multiple biological functions and multi-faceted cultural history. The compounds are classified into four different groups according to their biosynthetic origin: alkaloids, phenylpropanoids, polyketides, and terpenoids. Since more than 200,000 structures of natural products from plants are known, only selected groups and compounds are presented.

Access provided by Autonomous University of Puebla. Download chapter PDF

Natural product sciences: an integrative approach to the innovations of plant natural products

Article 14 September 2020

Phytochemicals: Diversity, Sources and Their Roles

Plant Secondary Metabolites: Functions in Plants and Pharmacological Importance

Keywords

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

1 Nitrogen-Containing Natural Products

The term alkaloid is derived from the Arabic word “al-qali” that refers to potassium carbonate-containing ashes from plant material. Traditionally, alkaloids are defined as heterocyclic nitrogen compounds biosynthesized from amino acids. Many other substances, however, that do not exactly match this rule are classified as alkaloids, either for historical reasons or due to their bioactivities. With currently more than 12,000 known structures, alkaloids represent one of the biggest groups of natural products. Due to this large number and the high structural diversity, it is impossible to give a comprehensive summary of all different types of alkaloids, and only some classes will be introduced. In addition to alkaloids, benzoxazinoids, glucosinolates, and cyanogenic glucosides will be presented. Like the alkaloids, these metabolites contain nitrogen and are derived from amino acids.

2 Purine Alkaloids

Purine alkaloids are nitrogen containing compounds derived from nucleoside metabolism (Ashihara and Crozier, 2001). The purine backbone is synthesized from several small molecules of primary metabolism that include L-aspartic acid, L-glutamine, L-glycine, and formate. Cytokinins, plant hormones that control, e.g., stem growth and differentiation, apical dominance, and senescence, are derived from the same pathway. Purine alkaloids are produced in a variety of taxonomically unrelated plant species, e.g., coffee (Coffea arabica and other Coffea species, Rubiaceae), tea (Camellia sinensis, Theaceae), cacao (Theobroma cacao, Sterculiaceae), maté (Ilex paraguariensis, Aquifoliceae), guaraná (Paullinia cupana, Sapindaceae), and cola (Cola nitida, Sterculiaceae). The most abundant purine alkaloid is caffeine, followed by theobromine and some minor purines, e.g., theophylline and paraxanthine (Fig. 1). Coffee seeds (“beans”) contain ca. 1% caffeine, young tea leaves 2-3% (Ashihara and Suzuki, 2004).

Since caffeine is accumulated in higher amounts than the other purines, its function in plants has been investigated. It may serve as defense against herbivores (Hollingsworth et al., 2002) and as autotoxin, because it inhibits the germination of coffee seedlings (Friedmann and Waller, 1985).

Caffeine is a central stimulant and widely consumed in beverages like coffee, tea, and sodas, but also in cold medicine and analgesics. The average daily caffeine consumption of adults is 280 mg; one cup of filter coffee contains ca. 140 mg caffeine, one cup of black tea ca. 80 mg (Lovett, 2005). Besides caffeine, theophylline is of interest, since it has found application in the therapy of asthma due to its bronchodilatory effect.

The predominant mode of action of caffeine and other purine alkaloids is the blockade of adenosine receptors resulting in the release of neurotransmitters (Benowitz, 1990). In higher concentrations, phosphodiesterase, the enzyme that hydrolyzes the second messenger cAMP, is inhibited. However, these blood concentrations are normally not reached by consumption of caffeine-containing beverages. More recently, the attention towards caffeine increased because coffee drinkers show a reduced risk for Parkinson’s disease (Ascherio et al., 2004).

C. arabica originated from Ethiopia, where the fruits were first used as food by nomads. Roasted coffee seeds (“beans”) were brewed in Arabia around AD 1000 to prepare a drink called “qahwah”, and it was introduced into Europe as “kahveh” after AD 1600 coffee and coffee houses became soon popular in Europe. Johann Sebastian Bach’s “Coffee Cantata” (BMV 211), which he composed for a text written by Picander in the beginning of the eighteenth century, reflects this growing popularity as well as the controversy on the assumed dangerous health effects of coffee at that time.

Tea is prepared from fermented (black tea) or unfermented (green tea), dried leaves of C. sinensis. The earliest records on tea drinking come from China in the first millennium BC. From there, it was introduced into Japan in the eighth century AD by Buddhist monks. Tea was first shipped to Europe by the Dutch East India Company in 1606.

The cacao tree (T. cacao, Sterculiaceae) originates from the Amazon Basin, but it was cultivated by the Mayas in Mesoamerica. Its seeds (“beans”) contain theobromine and caffeine. Mayas and Azteks used roasted cacao seeds together with chili peppers and other spices to prepare a drink, which the Aztecs called “xocoatl”. According to Aztec belief, cacao was given to humanity by the god Quetzalcoatl. The Swedish botanist Carl Linnaeus named the cacao tree after the Aztec tradition; Theobroma means “food of the gods” in Greek. The first cacao beans were brought to Europe by the Spanish Conquistador Hernán Cortés.

3 Tropane Alkaloids

Tropane alkaloids originate from the amino acids ornithine and/or arginine. They all have in common the bicyclic tropane skeleton that consists of a seven-membered ring with an N-bridge between C-1 and C-5, the nitrogen being methylated. Nortropanes lacking the N-methylation and seco-tropanes with a dissected N-bridge have been described, too (Griffin and Lin, 2000). Many tropane alkaloids are esters of the alcohols tropine (tropane-3α-ol) or pseudotropine (tropane-3β-ol) (Fig. 2) with aliphatic or aromatic acids. Tropane alkaloids were isolated first from the nightshade family (Solanaceae). Many structurally diverse tropanes, however, have been discovered in the related family Convolvulaceae, like the Solanaceae a member of the order Solanales, and in some species from the unrelated plant families Brassicaceae, Euphorbiaceae, Erythroxylaceae, Proteaeceae, and Rhizophoraceae (Griffin and Lin, 2000).

4 Hyoscyamine and Scopolamine

(S)-Hyoscyamine and (S)-scopolamine are esters of the amino alcohols tropine and scopine with (S)-tropic acid, which is derived from phenylalanine (Fig. 3). The two alkaloids occur exclusively in the Solanaceae family. They act as antagonists of muscarinic acetylcholine receptors (parasympatholytics) and lead to an increase in pulse rate, relaxation of smooth muscles, e.g., in the gastrointestine and the bronchial tract, reduction of salivary, bronchial, gastric, and sweat gland secretion. While hyoscyamine is a central stimulant, scopolamine depresses the central nervous system.

Atropine, the racemate of (S)- and (R)-hyoscyamine, is formed during the extraction of plant material. Although (S)-hyoscyamine is more effective than the (R)-enantiomer, atropine is more widely used for traditional reasons. In medicine, atropine is used against spasms during a biliary colic, as antidote against intoxication with organophosphorous insecticides, and as pre-medication before surgery to decrease salivation and respiratory secretion. (S)-Scopolamine is applied as treatment of motion sickness. Derivatives of hyoscyamine or scopolamine are used as mydriatics for eye examinations, as treatment for asthma and chronic obstructive bronchitis, and against gastrointestinal spasms.

Plants containing hyoscyamine and scopolamine have been used throughout history as psychoactive drugs, poisons, aphrodisiacs, and for the preparation of analgesic and sleeping potions. Famous examples include the deadly nightshade (Atropa belladonna), thorn-apple (Datura species), henbane (Hyoscyamus niger), and mandrake (Mandragora officinarum). All plants are toxic, and, for example, five to ten fruits of A. belladonna are lethal in an adult. This is reflected in the name “Atropa”, the Greek goddess of destiny who cuts the thread of life. “Bella donna” (Italian for “beautiful woman”) refers to the custom of Renaissance ladies who dilated their pupils with extracts of the deadly nightshade. Solanaceous plants with tropanes are often mentioned in literature, for example, in Homer’s Odyssey and several pieces by William Shakespeare.

Atropine was first isolated from A. belladonna (Mein, 1833), and (S)-hyoscyamine was extracted from H. niger (Geiger and Hesse, 1833). In the late nineteenth century, (S)-scopolamine was detected by Ladenburg (1881) and Schmidt (1892). Today, (S)-hyoscyamine and (S)-scopolamine are obtained from Duboisia leichhardtii and Duboisia myoporoides, trees native to Australia, and hybrids of the two species.

5 Cocaine

Cocaine is the benzoic acid ester of the tropane base methylecgonine. Only Erythroxylum coca and Erythroxylum novogranatense, shrubs or small trees native to the Andes, contain substantial amounts of cocaine in their leaves, i.e., up to 1% of their dry mass (Plowman and Rivier, 1983). If the coca leaves are dried or stored improperly, the cocaine content decreases rapidly. The two Erythroxylum species contain also other ecgonine derivatives, e.g., cis- and trans-cinnamoylcocaine and the truxillins, esters of methylecgonine with dimeric cinnamic acid (Fig. 4) (Griffin and Lin, 2000).

Cocaine is a highly addictive central stimulant that inhibits the re-uptake of the neurotransmitters dopamine and norepinephrine at synapses, and inhibits monoamine oxidase, the enzyme that degrades dopamine, epinephrine, and norepinephrine. This leads to euphoria, hyperactivity, suppression of hunger and fatigue. Peripheral effects include increased heart rate and blood pressure, dilation of pupils, hyperglycaemia, and hyperthermia (White and Lambe, 2003). If cocaine is applied on mucous membranes, it blocks Na⁺ channels leading to local anaesthesia. Therefore, cocaine is used as local anaesthetic in surgeries of the eye, ear, nose, and throat.

As an illegal drug, cocaine occurs in different forms. The hydrochloride is soluble in water and can be injected, sniffed, or chewed. “Freebase” is cocaine base, which is gained by extraction of cocaine from alkaline solutions with ether. It evaporates at high temperatures and can be inhaled by smoking. Another smokable form of the cocaine base is “crack”, which is obtained by precipitating cocaine hydrochloride from solution with baking soda.

In South America, the chewing of coca leaves has a long tradition and dates back to 3000 B.C. It is used to overcome exhaustion, hunger, and thirst, and presumably does not have the addictive potential of cocaine. The leaves are chewed together with an alkaline agent like plant ash or sodium bicarbonate, which converts the alkaloids to their free bases. Only a small portion of the cocaine is hydrolyzed to methylecgonine (Rivier, 1981).

Coca leaves were brought to Europe by the Spanish conquistadores, and cocaine was isolated from the leaves in the 1860s. In 1863, the French chemist Angelo Mariani created the tonic “Vin Mariani”, an extract of coca in Bordeaux wine. The non-alcoholic version “Coca-Cola” was invented in 1886 by the American Pharmacist John Pemberton, who mixed extracts of coca leaves and caffeine-containing cola nuts with soda. With the introduction of the first anti-drug laws in the USA in 1906, however, only decocainized leaves were used for the production of Coca-Cola.

6 Calystegines

Calystegines contain the nortropane skeleton with three to five hydroxyl groups. In contrast to most other tropane alkaloids, the hydroxyl groups are not esterified, but they can be glycosylated. The bridgehead C-1 of calystegines is hydroxylated, only in calystegine N₁ it is linked to an amino group instead (Dräger, 2004). The structures of the three most widespread calystegines are shown in Fig. 5. Calystegines were discovered in roots of Calystegia sepium (Tepfer et al., 1988), and the first structures were determined in 1990 (Goldmann et al., 1990). Since then, they have been isolated from numerous members of the Brassicaceae, Convolvulaceae, Erythroxylaceae, Solanaceae, and from two species of the Moraceae (Biastoff and Dräger, 2007). One important reason for their late discovery is their high hydrophily due to which they cannot be extracted with organic solvents like other alkaloids.

Calystegines are sugar-mimicking glycosidase inhibitors. Due to their structural similarity to sugars, they compete with polysaccharides for binding at the active site of the glycosidase. Therefore, one possible medicinal application for this group of metabolites is the prevention of post-prandial glucose peaks in patients with type II diabetes. In addition, calystegines might become useful for the therapy of Morbus Gaucher, a lysosomal storage disease that is caused by a mutation in the gene encoding glucocerebrosidase. Calystegines were reported to act as chaperones on the mutated enzyme thus preventing its misfolding and degradation. Nevertheless, it is still unclear whether these hydrophilic polyhydroxylated alkaloids can be absorbed in the intestines and transported to the lysosomes of target cells (reviewed by Biastoff and Dräger, 2007).

7 Pyrrolizidine Alkaloids

The backbone of pyrrolizidine alkaloids is composed of a hydroxymethylpyrrolizidine (necine base) that is mostly esterified with branched aliphatic mono- or dicarboxylic acids (necic acids). The necine base is biosynthesized from spermidine and putrescine, which in turn originates from arginine (Hartmann et al., 1988). The origin of the necic acids has been investigated only for pyrrolizidine alkaloids of the senecionine and lycopsamine type; they are derived from amino acid metabolism (Stirling et al., 1997; Weber et al., 1998). The major structural types of pyrrolizidine alkaloids are depicted in Fig. 6. In plants, these alkaloids are usually stored and transported as polar N-oxides. Pyrrolizidines occur mainly in the plant families Asteraceae, Boraginaceae, Fabaceae, and Orchidaceae, although scattered occurrences in other plant families have also been described (Hartmann and Ober, 2000).

Many pyrrolizidine alkaloids are hepatotoxic, mutagenic, and carcinogenic. They can cause veno-occlusive disease of the liver that may lead to cirrhosis and eventually liver failure. The main reasons for intoxications with pyrrolizidines are contamination of cereals with pyrrolizidine-containing plants and the ingestion of herbal medicines containing these alkaloids.

The structural features responsible for the genotoxicity are a double bond in the necine base between C-1 and C-2, presence of hydroxy groups at C-7 and C-9, and esterification of at least one of these hydroxy groups with a branched carbon chain (Frei et al., 1992). In most vertebrates and insect herbivores, the alkaloid N-oxides are reduced in the gut to their free bases. The reduced alkaloids are then taken up and bioactivated by cytochrome P450-dependent monooxygenases of the liver to highly reactive dehydropyrrolizidine alkaloids that react with nucleophilic groups of proteins and DNA (Röder, 1995).

Although pyrrolizidines are toxic, many insects feed on pyrrolizidine-containing plants. Several butterflies and moths (Lepidoptera) and some Chrysomelid leaf beetles (Coleoptera) are even able to sequester pyrrolizidine alkaloids as defense compounds against predators. Adult members of the Lepidoptera selectively ingest plants with pyrrolizidines, a behaviour called pharmacophagy. In the gut of adapted Lepidoptera, the N-oxides are reduced and taken up as free bases. In the hemolymph, however, they are detoxified by oxidation to the water-soluble N-oxides, which do not serve as substrates for bioactivating cytochrome P450 enzymes. In addition to their function in chemical defense in adapted butterflies, pyrrolizidine alkaloids also play an important role in the mating process. Male moths utilize pyrrolizidines to synthesize the pheromone hydroxydanaidal in order to signal their alkaloid load to the females. During courtship, male moths of the species Utetheisa ornatrix transfer sequestered pyrrolizidine alkaloids as a nuptial gift to the female. The female moth transfers her own pyrrolizidines and the alkaloids acquired during mating to the egg mass to protect the offspring (Eisner and Meinwald, 1995).

8 Quinolizidine Alkaloids

Quinolizidine alkaloids are biosynthesized from lysine via cadaverine. Apart from the bicyclic lupinine, most other compounds of this group are tri- or tetracyclic. Some representative structures are shown in Fig. 7. Quinolizidine alkaloids occur abundantly in the Fabaceae, but also in several unrelated taxa, e.g., Berberidaceae, Chenopodiacae, Ranunculaceae, Rubiaceae, and Solanaceae (Wink, 2002). Traces of quinolizidines were found in elicited cell cultures of species that normally do not produce these metabolites (Wink and Witte, 1983). This finding, together with the occurrence of quinolizidines alkaloids in taxonomically unrelated species, has lead to the hypothesis that the genes for the biosynthesis of quinolizidines are widely distributed in the plant kingdom, but are actively transcribed only in a few species that use them as feeding deterrents against herbivores.

The function of quinolizidines as defense compounds can be observed in the example of sweet lupins, an alkaloid-free breeding form. In contrast to the alkaloid-containing wild form, the bitter lupin, sweet lupins are more susceptible to herbivores (Wink, 2003). In addition to their function as defense compounds, a minor function of quinolizidines is nitrogen transport in the phloem and probably storage of nitrogen in seeds (Wink and Witte, 1984, 1985).

Quinolizidines have antiarrhythmic, CNS-depressant, hypotensive, and hypoglycemic effects. Their toxicity and some of their pharmacological properties can be explained through inhibition of Na⁺ and K⁺ channels and interaction with nicotinic and muscarinic acetylcholine receptors. Sparteine from broom (Cytisus scoparius) is used as antiarrhythmic. However, its medicinal use is declining and restricted because about 10% of all patients are unable to metabolize this alkaloid and suffer from intoxication (Wink, 2003).

Only few insects have adapted to quinolizidine alkaloids and sequester them as defense compounds, e.g., some aphids and larvae of the pyralid moth Uresiphita reversalis (Wink and Witte, 1991; Montllor et al., 1990). This is in contrast to pyrrolizidines, which are utilized by a large number of butterflies and beetles.

9 Alkaloids Derived from Tyrosine

The amino acid tyrosine is a precursor of numerous alkaloids. The largest group is formed by the benzylisoquinoline alkaloids. In addition, several other alkaloid classes originate from tyrosine, for example, the Ipecac alkaloids and the Amaryllidaceae alkaloids. The benzylisoquinolines, Ipecac- and Amaryllidaceae alkaloids will be reviewed.

10 Benzylisoquinoline Alkaloids

Benzylisoquinoline alkaloids are derived from two molecules of tyrosine. The central intermediate in their biosynthesis, (S)-reticuline, can undergo various rearrangements and modifications to yield the different structural classes of benzylisoquinolines (Fig. 8). At present, this diverse group of alkaloids comprises about 2,500 known structures. Benzylisoquinolines occur mainly in basal angiosperms, e.g., in members of the Berberidaceae, Fumariaceae, Papaveraceae, Menispermaceae, and Ranunculaceae, but also in other taxa.

Some benzylisoquinoline alkaloids have powerful pharmacological activities and have therefore found application in medicine, e.g., the analgesic morphine, the antitussive and analgesic codeine, the muscle relaxant tubocurarine, and the antimicrobial and anti-inflammatory sanguinarine. As can be expected from their highly diverse structures, these compounds have different mechanisms of action. Morphine and codeine are agonists at the μ-, δ-, and κ- opioid receptors, which are normally targeted by endorphines, enkephalines and dynorphines as endogenous ligands (Schiff, 2002). The bisbenzylisoquinoline alkaloid tubocurarine is the active principle of arrow poison from the liana Chondrodendron tomentosum, which is native to the Amazon Basin. Tubocurarine is an antagonist at nicotinic acetylcholine receptors on the neuromuscular end plate of skeletal muscle and is used to induce complete muscle relaxation before surgeries (Howland et al., 2005). Due to its quaternary nitrogen it is absorbed poorly and has to be injected intravenously.

Like tubocurarine, the quarternary benzophenanthridine sanguinarine is absorbed badly. It reacts with negatively charged and nucleophilic groups of proteins and inhibits several enzymes, e.g., Na⁺/K⁺-ATPase (Straub and Carver, 1975). In addition, it intercalates DNA due to its planar structure (Nandi and Maiti, 1985).

The opium poppy (Papaver somniferum) is an important medicinal plant with a colorful history. Opium, the dried latex of unripe capsules of P. somniferum, contains more than 80 isoquinoline alkaloids. The main alkaloids in opium are morphine (4-21%), followed by codeine, thebaine, papaverine, noscapine, and narceine (Dewick, 2002). The alkaloid concentrations vary strongly, and depending on the P. somniferum cultivar, also other alkaloids can occur in substantial amounts, e.g., oripavine in poppy from Tasmania (Frick et al., 2005). The only other plant species that accumulates the morphinans morphine and codeine is Papaver setigerum.

The opium poppy originated from the Mediterranean area. Earliest mention of the opium poppy, its cultivation, and the harvest of poppy latex are found on Sumerian clay tablets dating back to 3000 BC (Schiff, 2002). In ancient Greece, opium was used for medicinal and ritual purposes. The word “opium” is derived from the ancient Greek “opos” which means “milky juice of plants” (Askitopoulou et al., 2000). The twin brothers Hypnos and Thanatos, the Greek gods of sleep and death, are often depicted with opium poppies. Opium was mentioned by Homer in his “Iliad”, and by the famous Greek physicians Hippocrates and Galen (Schiff, 2002). In the Roman empire, opium gained importance not only as medicine, but also as poison. Agrippina, emperor Claudius’ wife, killed her stepson Brittannicus with an overdose of opium, so that her own son Nero could become emperor (Booth, 1998). Avicenna (980-1037), the famous Arab physician and scientist, recommended opium and plants of the nightshade family as analgesics and anaesthetics (Aziz et al., 2000). Arab traders brought opium to China, where it was first used only by the elite, but by the end of the seventeenth century by a large part of the Chinese population (Schiff, 2002). The high rate of addiction lead to a prohibition of opium by the Chinese government, but British merchants continued to smuggle opium into China. The conflict escalated in the Opium Wars (1839-1842 and 1856-1880), in which China was defeated and forced to allow the import of opium.

The sleep-inducing principle of opium was identified in 1806 by the German pharmacist Friedrich Sertürner. He succeeded in isolating crystalline morphine, which he named “morphium” after the Roman god of sleep “Morpheus” (Zenk and Jünger, 2007). It took more than 100 years, until the chemical structure of morphine was elucidated (1924-1925) by Gulland and Robinson. Total synthesis of morphine turned out to be extremely difficult due to its five stereo centers, and it was achieved by Gates and Tschudi (1952).

Since no cost-efficient synthesis of morphine and codeine has been developed, these alkaloids are isolated from “poppy straw”, which consists of the entire plant tops (Dewick, 2002), and from opium. Legal cultivation of P. somniferum is carried out in India, Turkey, Russia, and Australia. Today, nearly all illegally produced opium (93%) originates from Afghanistan; smaller amounts are produced in South East Asia and South America (Sanderson, 2007; World Drug Report, 2007).

11 Ipecac Alkaloids

Ipecac alkaloids are derived from the amino acid tyrosine and the monoterpene secologanin and are therefore termed terpenoid-isoquinoline alkaloids. They occur in the eudicot families Alangiaceae and Rubiaceae. Two species, Psychotria ipecacuanha (Rubiaceae) and Alangium lamarckii (Alangiaceae), have been investigated in detail with respect to their metabolites and biosynthesis of their alkaloids (Fujii and Ohba, 1998). Roots and rhizomes of P. ipecacuanha are the source of cephaeline and emetine (Fig. 9), two compounds with emetic, expectorant, and amebicidal properties. The emetic effects are presumably mediated by 5-hydroxytryptamine 3 (5HT₃) receptors (Hasegawa et al., 2002). Ipecacuanha syrup is used to induce emesis after accidental ingestion of poisons. In lower doses, the extract of P. ipecacuanha roots is used as expectorant.

P. ipecacuanha occurs in the rainforests of Meso and South America. It was traditionally used in the Brazilian folk medicine. In the seventeenth century, the plant was brought by traders to France, and soon it found application in Europe as treatment against dysentery. The British physician Thomas Dover invented a special preparation P. ipecacuanha that was named Dover’s powder after him. It consisted of Ipecacuanha root, opium, and potassium sulphate and was used as diaphoretic and medicine against cold and fever.

12 Amaryllidaceae Alkaloids

The Amaryllidaceae alkaloids are restricted to the monocot family that coined their name. They are derived from one molecule of tyrosine and protocatechuic aldehyde, which originates from phenylalanine. The central intermediate of their biosynthetic pathway is norbelladine. Nearly 500 structures of Amaryllidaceae alkaloids are known, and some of them possess significant pharmacological activities (Jin, 2007) (Fig. 10). For example, the isocarbostyrils pancratistatin from the spider lily (Hymenocallis littoralis) and narciclasine from Narcissus species show promising antineoplastic properties (Dumont et al., 2007; McLachlan et al., 2005). Lycorine that occurs, e.g., in Clivia, Crinum and Galanthus species exhibits antiviral activity (Ieven et al., 1983; Szlávik et al., 2004).

Galanthamine is the only alkaloid of this class that has already found application in medicine. It is approved for the symptomatic treatment of Alzheimer’s disease in Europe and the United States. Its mode of action consists in a competitive and reversible inhibition of acetylcholinesterase, which leads to an increased concentration of acetylcholine at neuronal synapses. In addition, galanthamine acts as an allosteric modulator on nicotinic acetylcholine receptors. Since a characteristic feature of Alzheimer’s disease is the loss of acetylcholinergic neurons concomitant with decreased levels of acetylcholine, galanthamine can, at least partially, compensate the damage and thus enhance cognitive functions in Alzheimer’s patients.

Galanthamine was isolated first from the Caucasian snowdrop (Galanthus woronowii) in the early 1950s. Most of the early research on galanthamine was carried out in Bulgaria and the USSR during the Cold War. Initially, galanthamine was used to reverse neuromuscular blockade induced by muscle relaxants and for the treatment of post-polio paralysis. After it was discovered that galanthamine passes the blood brain barrier, the interest in this drug increased, and it was eventually established as treatment for Alzheimer’s disease (Heinrich, 2004).

Galanthamine occurs in the bulbs of Galanthus, Narcissus, and Leucojum species, where it accumulates in concentrations of 0.05-0.2% (Dewick, 2002). Initially, it was isolated from these plant species. In 1999, a feasible and economic protocol for the industrial synthesis of galanthamine was developed by the groups of Fröhlich and Jordis in collaboration with Sanochemia (Küenburg et al., 1999).

13 Monoterpene Indole Alkaloids

This class of alkaloids is biosynthesized from tryptophan and secologanin via the central intermediate 3α(S)-strictosidine. Over 2,000 structurally diverse monoterpene indole alkaloids are known, and among them are several pharmacologically valuable compounds (O’Connor and Maresh, 2006). Some representative structures of the major classes of monoterpene indole alkaloids are depicted in Fig. 11. These alkaloids are mainly found in the plant families Apocynaceae, Loganiaceae, Nyssaceae, and Rubiaceae. The following section will focus on some representative alkaloids with significant pharmacological activities.

13.1 Rauwolfia Alkaloids

The Indian snakeroot, Rauwolfia serpentina (Apocynaceae), is a shrub that grows in southern and southeast Asia. The root of this plant has been used traditionally in Ayurvedic medicine (Sanskrit name: “Sarpagandha”) to treat hypertension and mental disorders. In the 1950s, the blood pressure lowering agent was identified as reserpine, a monoterpene indole alkaloid of the yohimbine class. Reserpine inhibits a proton pump that is responsible for maintaining a high concentration of protons in neuronal vesicles. If the proton pump is inhibited, neurotransmitters like dopamine and norepinephrine can no longer be stored in the vesicles. Thus, the neurons are depleted of their transmitters, which leads to a decrease in blood pressure and sedation. Due to serious negative side effects, in particular depression, reserpine has mainly been replaced by other drugs, but is still used in some combinations with other antihypertonics. In addition, extracts of Rauwolfia roots are used in herbal remedies against hypertension.

The roots of R. serpentina contain 0.7–2.4% monoterpene indole alkaloids (Dewick, 2002). In addition to their main alkaloid reserpine, they also produce other pharmacologically active alkaloids, e.g., the antihypertensive ajmalicine and the antiarrhythmic ajmaline. Ajmaline blocks Na⁺ channels in the heart and thus prolongs intraventricular conduction times.

13.2 Catharanthus Alkaloids

The Madagascar periwinkle (Catharanthus roseus, Apocynaceae, formerly known as Vinca rosea) is a small subshrub or herbaceous plant native to Madagascar. It contains about 130 monoterpene indole alkaloids of different subclasses (van der Heijden et al., 2004). Nowadays, C. roseus occurs worldwide in subtropical and tropical regions. It is cultivated as an ornamental plant, but it has also found application in the folk medicine of various countries. Because the plant was used as an antidiabetic in Jamaica, it was screened for hypoglycaemic activity by Eli-Lilly, USA, and the Cancer Research Center, Canada, in the late 1950s. Although plant extracts proved to be ineffective against diabetes, scientists of both institutes independently discovered the anticancer activity of several bisindole alkaloids, in particular, vinblastine and vincristine (reviewed by Noble, 1990). These compounds bind tubulin and inhibit its polymerization, thus hindering the formation of the mitotic spindle and causing cell cycle arrest at metaphase in dividing cells (Jordan et al., 1991). Vinblastine is used as therapy against Hodgkin’s disease and non-Hodgkin’s lymphomas. Its major side effect is a suppression of the bone marrow. Vincristine is more powerful but also more neurotoxic than vinblastine. It is used to treat acute lymphatic leukaemia, non-Hodgkin’s lymphomas, rhabdomyosarcoma, and Wilms tumor. Two semisynthetic analogs with less side effects than the two Vinca alkaloids, vinorelbine and vindesine, are used as to treat non-small cell lung cancer and breast cancer. Vindesine is also used as chemotherapeutic for lymphoma, acute leukaemia, and melanoma.

Initially, vincristine and vinblastine were isolated from leaves of the Madagaskar periwinkle, however, the yield was very low. The plant tissue contains only 0.0002% vinblastine (Noble, 1990), and the vincristine content is even lower. Therefore, a partial synthesis for the dimeric indole alkaloids was developed starting from the monomers vindoline and catharanthine (Dewick, 2002).

14 Camptothecin

Camptothecin (Fig. 11) belongs to the quinoline class of the monoterpene indole alkaloids. Although it lacks the indole ring, feeding studies proved that it originates from tryptamine and a monoterpene precursor, and the indole structure undergoes rearrangements to a quinoline heterocycle (Hutchinson et al., 1974; Sheriha and Rapoport, 1976). The alkaloid occurs in several unrelated eudicot species, e.g., Camptotheca acuminata (Nyssaceae), Ophiorrhiza pumila (Rubiaceae),Ervatamia heyneana (Apocynaceae), and Nothapodytes foetida (Icacinaceae).

Camptothecin is unique in its mechanism of action. It binds to the cleavable complex of topoisomerase I and covalently attached DNA and stabilizes it (Hsiang et al., 1985). This non-degradable DNA/topoisomerase I complex arrests the replication fork and thus kills cells by inhibition of DNA synthesis (Hsiang et al., 1989). Camptothecin and its derivatives are therefore also termed topoisomerase “poisons”.

Camptothecin was isolated first in 1966 (Wall et al., 1966) from Camptotheca acuminata, a tree native to China and Tibet, also known as “Happy Tree” (chinese “xi shu”). Despite the promising anticancer activities, the poor solubility of the alkaloid presented a major obstacle to clinical application. Water-soluble derivatives were prepared by opening the lactone ring. During clinical trials, however, it became apparent that the anticancer activity of these analogs was greatly decreased, and the trials were abandoned. Only later it became known that the anticancer activity of camptothecin is dependent on the intact lactone ring. The interest in camptothecin returned in 1985 after its unique mechanism of action became known. This encouraged the synthesis of water-soluble analogs that retained the activity. At present, two derivatives of camptothecin are used in cancer chemotherapy. Irinotecan (syn. CPT-11) is used to treat colon cancer in combination with other chemotherapeutics; and topotecan is approved as therapy of ovarian and small-cell lung cancer. Several new camptothecin derivatives are currently tested in clinical trials (reviewed by Sirikantaramas et al., 2007).

Camptothecin derivatives are produced semisynthetically using the alkaloids extracted from intact plants of C. acuminata or N. foetida. Alternatives to this limited resource have been suggested. For example, young leaves of C. acuminata accumulate high levels of alkaloids (4-5 mg/g dry weight; López-Meyer et al., 1994) and can be harvested repeatedly without killing the trees. In addition, the clonal propagation of elite cultivars by shoot and bud culture of C. acuminata (Vincent et al., 1997) or hairy roots of Ophiorrhiza pumila (Sudo et al., 2002) might present a suitable solution to overcome the shortage in plant material. Recently, camptothecin production was detected in the endophytic fungi Entrophospora infrequens of N. foetida (Puri et al., 2005; Amna et al., 2006), and this may open a new source for the commercial production of the antineoplastic alkaloid.

14.1 Cinchona Alkaloids

The genus Cinchona (Rubiaceae) comprises about 25 species of tall, evergreen trees that grow in South America. The bark of these trees accumulates quinoline alkaloids that are, like camptothecin, derived from tryptophan and secologanin. Cinchona alkaloids are also found in the genus Remijia of the Rubiaceae family.

The Cinchona bark was called “Quina-Quina”, which means “bark of barks”, in the native Indian language Quechua. It was discovered by Spanish monks in Peru around 1630. They either learned to use the bark against fevers from the indigenous Indian population or discovered its application by themselves (Bruce-Chwatt, 1988). Cinchona bark was introduced to Europe by Jesuits, where it became known as “Jesuits’ powder” and was used to cure malaria, which was then widespread in Europe. However, initially the use of Cinchona powder was controversial. Due to its approval by the Vatican, Protestants refused to take it. In addition, healing of malaria with a hot, bitter drink form a powdered bark contradicted the humoral theory of the antique Greek philosophers, which was at that time still the base for medicinal treatment. Moreover, often bark of bad quality or adulterated bark was sold that proved to be inefficient. Cinchona bark became only widely accepted after the English apothecary apprentice Robert Talbor applied it successfully as a secret formula to cure many members of European royalty from malaria, among them the English King Charles II and the son of the French King Louis XIV. After Robert Talbor’s death it was disclosed that his secret remedy was based on Cinchona bark (Bruce-Chwatt, 1988; Kaufman and Rúveda, 2005). Quinine (Fig. 11) was isolated from the bark of Cinchona trees in 1820 by the French pharmacists Pelletier and Caventou, and its molecular formula was established in 1854 by Adolf Strecker.

For two centuries, Cinchona bark was obtained solely from South America. It was particularly valuable for the colonial powers because malaria was frequent in Asia and Africa. Due to the high demand for the drug and the dwindling natural resources, efforts were taken to cultivate the trees outside South America. In the middle of the eighteenth century, the Dutch and English succeeded in growing Cinchona trees in Java and India. Shortage of quinine in World Wars I and II due to trade embargos encouraged the development of synthetic analogs, e.g., the 4-aminoquinolines chloroquine and mefloquine, and the 8-aminoquinoline primaquine. A formal synthesis of quinine was achieved by Woodward and Doering (1944), however, due to the four stereocenters in the quinine molecule it is a very complex synthesis and commercially not feasible.

Today, three Cinchona species are cultivated for the production of quinine. C. succirubra yields the “red bark”, C. legderiana the “brown bark”, and C. calisaya the “yellow bark” (Dewick, 2002). In addition to quinine, the barks contain significant amounts of three other quinoline alkaloids: quinidine, the diastereomer of quinine, which is used as an antiarrhythmic, and 6-demethoxy analogs of the two alkaloids, cinchonine and cinchonidine.

Quinine and its analogs act on erythrocytic stages of Plasmodium falciparum, the causative agent of malaria. It is assumed that these antimalarial agents inhibit the polymerization of haematine, which is released upon the degradation of haemoglobin and is toxic for the parasite, into non-toxic hemozoin (Chou et al., 1980; Sullivan et al., 1996).

Since quinine is extremely bitter, gin was added to make it easier to drink, giving rise to the cocktail “gin and tonic” that nowadays contains only minute amounts of the alkaloid. In addition to tonic water, quinine is also an ingredient of other beverages, e.g., bitter lemon or vermouth.

15 Benzoxazinones

Benzoxazinones are derived from indole-3-glycerol phosphate, a molecule that is also the direct precursor of tryptophan. In the literature, acronyms derived from the substitution pattern of the benzoxazinone ring are often used to distinguish individual members of this class. For example, DIMBOA is 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one. Benzoxazinones occur mainly in the monocot Poaceae family, but also in some families of eudicot plants, e.g., Ranunculaceae, Acanthaceae, and Plantaginaceae. At present, it is still being investigated whether the pathway developed only once or several times independently after the divergence of moncots and dicots (Sicker et al., 2000).

Two characteristic structural features are found in all benzoxazinones: a cyclic hemiacetal in combination with a cyclic hydroxamic acid or a cyclic lactam (Fig. 12); the hydroxy function of the hemiacetal is usually glucosylated. In the intact plant tissue, these benzoxazinone glucosides are stored in the vacuole, whereas a specific glucosidase is located in plastids. Only after injury of the plant tissue, glucosides and glucosidases are released, and free aglucones are formed. Those benzoxazinone aglucones that contain a hydroxamic acid function are chemically instable, and their tautomeric open-ring form can be converted to benzoxazolinones under loss of one carbon as formic acid (Fig. 12).

Benzoxazinones act as pre-formed defense and possess antibacterial, antifungal, and antialgal properties (Bravo and Lazo, 1993, 1996). In addition, they serve as feeding deterrents and reduce the vitality of pests. In particular, these metabolites confer resistance to one of the major corn pests, the European corn borer (Ostrinia nubialis) (Grombacher et al., 1989). Only benzoxazinones with hydroxamic acid function show these bioactivities. An electron-donating hydroxy or methoxy group at C-7 increases the reactivity. The mode of action of benzoxazinones can be explained by modification of amino and thiol groups of biomolecules. The aldehyde function of the tautomeric open-ring form can react as an electrophile with NH₂ groups and form Schiff bases (Pérez and Niemeyer, 1989). Thiol groups can be oxidized by the cyclic hydroxamic acid form, which is in turn reduced to a lactam. Structural prerequisite for this oxidation is an electron-donating substitution at C-7 of the benzoxazinone skeleton (Atkinson et al, 1991). Benzoxazinoids that have been bio-activated by N-acetylation may act as alkylating agents towards nucleic acids and proteins (Hashimoto and Shudo, 1996).

Due to their toxicity, benzoxazinones can also function as allelochemicals (Sicker et al., 2000) and are therefore discussed as natural herbicides.

16 Cyanogenic Glycosides

Cyanogenic glucosides are β-glucosides of α-hydroxynitriles (syn. cyanohydrins), which are derived from the five proteinogenic amino acids phenylalanine, tyrosine, valine, isoleucine, leucine and the non-proteinogenic amino acid cyclopentenyl-glycine. Because of the stereo-center in the α-hydroxynitrile function, (R)- and (S)-forms of several cyanogenic glucosides exist. About 2,500 different plant species including ferns, gymnosperms, and angiosperms produce cyanogenic glucosides (Hegnauer, 1986; Seigler, 1991). Despite their widespread occurrence, these natural products are found predominantly in the families Araceae, Asteraceae, Euphorbiaceae, Fabaceae, Passifloraceae, Poaceae, and Rosaceae (Dewick, 2002). Some of the most abundant molecules are amygdalin (Rosaceae), linamarin and lotaustralin (Fabaceae), and the epimers dhurrin and taxiphyllin in the genus Sorghum (Seigler, 1991).

Like the benzoxazinones, cyanogenic glucosides belong to the preformed defense of the plant and are stored in the vacuole. Upon disruption of the plant tissue, they are degraded by β-glucosidases to the corresponding α-hydroxynitriles, which are hydrolyzed by α-hydroxynitrile lyases to aldehydes or ketones and toxic hydrogen cyanide (HCN) (Fig. 13). Since the α-hydroxynitriles are unstable, they can also decompose spontaneously, but the enzyme catalyzed reaction proceeds up to 20 times faster (Selmar, 1999). In the gut of herbivores, the β-glucosidic bond can also be hydrolyzed by intestinal bacteria. The toxicity of hydrogen cyanide can be explained by its affinity to metal ions. Cyanide ions complex iron (III) in the active site of cytochrome oxidase and thus inhibit the respiratory chain. Mammals can consume small amounts of cyanogenic glucosides and detoxify them, mainly via the liver enzyme rhodanese that converts cyanide to thiocyanate. Chronic intake of non-lethal amounts, however, can result in paralysis of legs (Konzo) or neurological disorders due to cyanide intoxication or iodine deficiency caused by accumulation of the iodine antagonist thiocyanate (Selmar, 1999). Intoxications by cyanogenic glucosides are often observed in populations that live on a diet poor in protein with insufficient supply of sulfur-containing amino acids, which are required for the detoxification of cyanide.

Cyanogenic glucosides act as feeding deterrents. Herbivores are probably rejected by the keto or aldehyde compound that arises after cleavage rather than by the cyanide (Jones, 1988). By transferring all genes required for the formation of the cyanogenic glucoside dhurrin from Sorghum bicolor into Arabidopsis, Tattersall et al. (2001) proved that cyanogenic glucosides play a role in plant defense. In comparison with wild-type leaves, leaves of transgenic Arabidopsis plants producing dhurrin were hardly consumed by the yellow-striped flea beetle (Phyllotreta nemorum). Despite the toxicity of the cyanogenic glucosides, several herbivores, especially insects, are able to feed on plants containing these natural products, and in this case the toxic compounds may act as phagostimulants. Some species of beetles, centipedes, and millipedes, but particularly many moths and butterflies sequester cyanogenic glucosides as defense compounds. The compounds are either taken up by feeding on cyanogenic plants or synthesized de novo by endogenous enzymes. In contrast to vertebrates, these arthropod species detoxify cyanide not by rhodanese, but mostly via β-cyanoalanine synthesis, a mechanism that is also used by plants (reviewed by Zagrobelny et al., 2008).

It has been postulated that cyanogenic glucosides also serve as storage compounds for reduced nitrogen and sugar (Selmar et al., 1988; Sánchez-Pérez et al., 2008). This has been deduced from the observation that cyanogenic glucosides are degraded during seed development or germination.

Interestingly, many important food crops accumulate cyanogenic glucosides (Jones, 1998), but usually not in the portion of the plant that is consumed. Some plants, however, contain high levels of these toxic constituents in the parts that are eaten, e.g., bamboo, cassava, lima beans, and sorghum. This problem is particularly serious in the case of cassava (Manihot esculenta), which is a major crop in many tropical countries. Cassava roots contain between 10 and 500 mg of cyanide equivalents per kg fresh weight (O’Brien et al., 1991) and have to be processed carefully to remove the toxic metabolites. Unfortunately, this treatment usually results in loss of protein, minerals, and vitamins. Various approaches to produce transgenic cassava with reduced content of cyanogenic glucosides in roots are currently underway (Jørgensen et al., 2005; Siritunga and Sayre, 2007).

17 Glucosinolates

Glucosinlates are β-thioglucosides of (Z)-N-hydroximinosulfate esters (Fig. 14). They are derived from the aliphatic amino acids alanine, isoleucine, leucine, methionine, and valine or from the aromatic amino acids phenylalanine, tryptophan, and tyrosine and share the first steps of cyanogenic glucoside biosynthesis. About 120 different structures of glucosinolates are known (Fahey et al., 2001). They occur exclusively in sixteen eudicot families, the majority belonging to the order Brassicales. Many of these plants are cultivated and consumed as vegetables or spices, e.g., cabbage (Brassica oleraceae, Brassicaeae), capers (Capparis spinosa, Capparidaeae), mustard (Sinapis alba, Brassicaeae), and wasabi (Wasabia japonica, Brassicaeae). The strong or pungent flavor of these plants can be explained by the presence of glucosinolates. If the plant tissue is damaged, the glucosinolates are hydrolyzed by myrosinase, a thioglucosidase that is spatially separated in the undamaged tissue. The resulting unstable thiohydroximate-O-sulfate intermediates undergo non-enzymatic loss of sulfate and spontaneous rearrangement to various bioactive products like isothiocyanates, nitriles, oxazolidine-2-thiones, epithionitriles, and thiocyanates (Halkier and Gershenzon, 2006) (Fig. 14). Hydrolysis of glucosinolates can also occur in the intestine of humans by myrosinases of the gut microflora.

The main product of the “mustard bomb” consisting of glucosinolates and myrosinase are isothiocyanates. These compounds are also responsible for many of the biological effects of glucosinolates, e.g., antibacterial, antifungal, nematicidal, and feeding deterrent activities (Fahey et al., 2001). The formation of hydrolysis products distinct from thiocyanates depends on the structure of the glucosinolates, pH, and the presence or absence of Fe²⁺ ions or specifier proteins. Specifier proteins do probably not possess catalytic activity, but may modulate myrosinase activity allosterically to yield nitriles, epithionitriles, or thiocyanates as degradation products instead of thiocyanates (Wittstock and Burow, 2007). Epithionitriles are produced only from glucosinolates with a terminal double bond. Indolyl glucosinolates are hydrolyzed to unstable indole isothiocyanates that give rise to the alcohol indole-3-carbinol and a variety of other products. Hydrolysis of β-hydroxyalkenyl glucosinolates yields oxazolidine-2-thiones that can cause goitre by inhibiting the incorporation of iodine into thyroid hormones. A crop particularly rich in goitrogenic glucosinolates is rape (Brassica napus), an important source of vegetable oil. To make the protein rich seed cake that remains after extraction of the oil suitable as animal foodstuff, rape plants with low levels of glucosinolates have been developed by breeding efforts (Fahey et al, 2001).

Glucosinolates from Brassicaceae vegetables (e.g., broccoli, cauliflower, Chinese cabbage, kale, kohlrabi, mustard) are discussed as cancer preventive agents. In particular, sulforaphane and indole-3-carbinol, the degradation products of glucoraphanin and glucobrassicin, respectively, show promising activities, e.g., stimulation of apoptosis. Sulforaphane enhances the excretion of cancerogenous compounds by inducing phase II detoxification enzymes like glutathione-S-transferase, UDP-glucuronosyl transferase, and NADPH quinone oxidoreductase. Indole-3-carbinol may prevent estrogen-sensitive cancers by increasing the ratio of weak to strong estrogens, but it may also possess cancer-promoting activities. Although some epidemiological studies suggest that a diet rich in glucosinolates can reduce the risk of cancer, it has not yet been unambiguously proven. In addition, the bioavailability of glucosinolates may be influenced by genetic polymorphisms that lead to a slower excretion of these compounds (Higdon et al., 2007).

Although glucosinolates act as feeding deterrents, many insect herbivores feed on plants containing these natural products. Two very different mechanisms for the detoxification of glucosinolates are known from two insect species. The diamond-black moth (Plutella xylostella) produces a sulfatase that cleaves the sulfate from glucosinolates and converts them to compounds that cannot be degraded by myrosinases (Ratzka et al., 2002). The cabbage white butterfly (Pieris rapae) contains a specifier protein that transforms glucosinolates in the presence of myrosinase to nontoxic nitriles that are excreted with the feces (Wittstock et al., 2004). Both detoxifying enzymes are expressed in the gut of the insects, the organ in which the glucosinolates would normally be degraded to isothiocyanates. Other insect herbivores sequester glucosinolates and use them for their own defense. This requires either an endogenous myrosinase that is spatially separated from the glucosinolates in the insects or myrosinases from the gut microflora of their enemies (Halkier and Gershenzon, 2006).

18 Natural Products Derived from the Shikimate Pathway and Phenylpropanoids

The shikimate pathway provides the precursors for benzoic acid derivatives and phenylpropanoid compounds in plants (Fig. 15). Shikimate is biosynthesized from D-erythrose-4-phosphate and phosphoenolpyruvate, two metabolites derived from the pentose phosphate cycle and glycolysis, respectively. Shikimate is further converted to chorismate by addition of a C₃ unit from phosphoenolpyruvate; and chorismate serves as precursor of the aromatic amino acids L-phenylalanine, L-tyrosine, and L-tryptophan.

An intermediate of the shikimate pathway, most likely 5-dehydroshikimate, is the precursor of gallic acid and the gallotannins (Werner et al., 1997), which are esters of glucose with several molecules of gallic acid. Gallotannins have been used for centuries for the tanning of hides and for the preparation of ink from ferrous sulfate and oak gall extract.

Since the shikimate pathway occurs only in plants and microorganisms, L-phenylalanine, L-tyrosine, and L-tryptophan are essential for animals and have to be taken up with food. L-Phenylalanine, and in monocots also L-tyrosine, are the precursors of the phenylpropanoids. This class comprises cinnamic acid derivatives, lignin, lignans, phenylpropenes, and coumarins, which all share the basic C₆-C₃ skeleton. Phenylpropanoids are aromatic compounds, often with a hydroxy group in the para position. If more than one hydroxy group is present at the aromatic ring, the new hydroxy function is usually positioned next to the first hydroxy group (ortho position). Phenylpropanoids with additional carbons derived from acetate units, e.g., the flavonoids, will be discussed together with the polyketides.

19 Lignans and Lignins

Lignans and lignins are both composed of the hydroxy cinnamic alcohols (monolignols) p-coumaryl alcohol, coniferyl alcohol, and sinapyl alcohol (Fig. 16). Lignans are formed by stereoselective coupling of two hydroxy cinnamic alcohols units and lignins are polymers of monolignols.

After incorporation into the polymer lignin, the monolignols p-coumaryl alcohol, coniferyl alcohol, and sinapyl alcohol are also referred to as H (p-hydroxyphenyl), G (guaiacyl), and S (syringyl) units, respectively.

Lignin from gymnosperms consists mainly of G units and low levels of H units. Eudicots and monocots utilize all three monolignols, although lignin from eudicots consist mainly of G and S units (Boerjan et al., 2003). Recently, it became evident that also other phenolic monomers, in particular acylated monolignols, are incorporated into lignin. In the lignin polymer, the alcohols are connected by various bonds comprising ether and carbon-to-carbon linkages. In addition, lignin can be interconnected with hemicelluloses of the cell wall (Sun et al., 2005). Although the monolignol composition of lignins can be determined, their exact structure has not yet been elucidated due to the large size and complexity of the polymers (Davin and Lewis, 2005). The function of lignin is to reinforce the cell walls together with the sugar polymers cellulose and hemicellulose. Lignification of cell walls is required to strengthen the vascular tissue and evolved ca. 400 million years ago in the Silurian with the emergence of the first vascular plants. After cellulose, lignin is the second most abundant biopolymer on earth. From an economic point of view, lignin is important for the quality of wood, but it is an undesirable component for the paper industry, because its oxidation leads to yellowing of paper. Lignin cannot be digested by ruminants and therefore decreases the digestibility of forage and the absorption of nutritients (Boerjan et al., 2003; Rouhi et al., 2000). In addition, lignin has to be removed from lignocellulose-containing plant material prior to the production of biofuels, because it hinders the degradation and extraction of cellulose. Possible strategies to improve biofuel production from lignocellulose are the generation of genetically modified crops with altered lignin content or composition and the use of lignin degrading enzymes from fungi or bacteria (Weng et al., 2008).

Lignans are formed by stereoselectively linking two monolignols at the central atoms of their side chains. If the monolignols are produced by other types of coupling, the dimers are termed neolignans (Dewick, 2002). In norlignans, the last carbon of one side chain of a monolignol is missing in the dimer. Lignans were found in more than 70 plant families, and because of their antiviral, antibacterial, and antifungal properties they presumably act as defense against herbivores and pathogens (Saleem et al., 2005). In addition, they occur in many plant foods like oil seeds, whole cereals, fruits and vegetables. A particular rich source of lignans with more than 0.3 g/100 g are flaxseed and sesame seed with secoisolariciresinol (Fig. 17) and sesamine as main constituents, respectively (Adlercreutz, 2007; Milder et al., 2005). These latter and several other lignans can be converted by the intestinal microflora to the mammalian lignans enterodiol and enterolactone (Fig. 17). The two enterolignans are weak phytoestrogens; they increase the concentrations of sex hormone binding globulin in the plasma and modulate steroid hormone concentrations by competing for their metabolizing enzymes (Adlercreutz, 2007). It is assumed that consumption of a diet rich in lignans benefits health and reduces the risk for colon and breast cancer. Since lignan-rich food usually contains other health-promoting ingredients like fibers or other polyphenols, it is difficult, however, to attribute the beneficial effects solely to lignans.

A strong cytotoxic lignan is podophyllotoxin (Fig. 17) from Podophyllum peltatum or P. hexandrum (Berberidaceae). Podophyllotoxin has the same mechanism of action as the terpene indole alkaloids vinblastine and vincristine; it inhibits cell division by binding to tubulin and preventing its polymerization. This lignan is used as treatment for warts, but is too toxic for systemic application. Derivatives with reduced toxicity are etoposide, etopophos, and teniposide. They are prepared semi-synthetically from 4’-demethylpodophyllotoxin and have an inverted stereochemistry at C-4. These changes lead to a new anticancer mechanism, the stabilization of topoisomerase-DNA complexes, which is similar to that of camptothecin. Unlike camptothecin, however, the podophyllotoxin analogues attack topoisomerase II, not topoisomerase I. Etoposide and its prodrug teniposide are used in combination with other drugs to treat small cell lung cancer, testicular cancer, and certain lymphomas. Teniposide is used as therapy for childhood acute lymphocytic leukemia.

20 Phenylpropenes and Benzenoids

Phenylpropenes are derived from cinnamic acid and share the first steps of lignin/lignan biosynthesis. Shortening of the cinnamic acid side chain by two carbons leads to compounds with a C₆-C₁ skeleton called benzenoids. Other volatile phenylpropanoid-related compounds are phenylacetaldehyde and 2-phenylethanol. They originate from phenylalanine which is shortened by one carbon (Pichersky and Dudareva, 2007). Phenylpropene and benzenoid volatiles are lipophilic compounds with a characteristic scent. They constitute the second largest group of plant volatiles after terpenoids. In many plants, phenylpropanoid/benzenoid and terpenoid volatiles occur as mixture, although usually one group accumulates predominantly. In addition to these two large groups of natural products, many other volatiles of plant origin are derivatives of amino acids and fatty acids. Each plant has its own cocktail of volatiles that is used for the attraction of pollinators and seed dispersers or as defense compounds. The defense function can be fulfilled either by directly deterring or intoxicating herbivores, or indirectly by attracting insect predators in case of tritrophic interactions or by communicating the danger to other plants in the neighborhood (Dudareva et al., 2006). In addition, many volatiles have antibacterial and antifungal properties (Kalemba and Kunicka, 2003).

Essential oils with phenylpropenes are found, e.g., in the Apiaceae, Lauraceae and Myrtaceae families. Many of these phenylpropene-containing plants have been employed by humans since antiquity as condiments and herbal remedies. Cloves, the unopened flower buds of the evergreen clove tree (Syzygium aromaticum, Myrtaceae) native to the Maluku islands, are used as spice, but also as anaesthetic and antiseptic in dentistry. The active ingredient and major component of essential oil from cloves is the phenylpropene eugenol (Fig. 18). Another evergreen tree of the tropics, Cinnamo-mum ceylanicum (Lauraceae) from Sri Lanka, is the source of cinnamon bark with trans-cinnamaldehyde as main flavor component. Cinnamon was highly priced in the antique world. The roman emperor Nero is said to have spent a year’s supply of cinnamon for the funeral of his wife Poppaea Sabina (Klein, 1987). Some phenylpropenes are potentially carcinogenic, e.g., safrole, methyleugenol, and estragole. They require bioactivation including hydroxylation and sulfation at the side chain to become toxic (Zhou et al., 2007).

Benzenoids contribute to characteristic fragrance of many flowers. Methyl benzoate, for example, is a major scent constituent of Petunia flowers. Other benzenoids that frequently contribute to floral scents are benzaldehyde, benzyl alcohol, benzyl acetate, and methyl salicylate (Fig. 18) (Knudsen et al., 1993). The latter compound is responsible for the characteristic smell and the analgesic effect of wintergreen (Gaultheria procumbens, Ericaceae) (Dewick, 2002).

21 Polyketides

Polyketides are synthesized from two-carbon units derived from activated acetate in the form of acetyl-CoA and malonyl-CoA. Unlike fatty acids, which also originate from these precursors, polyketides retain all or most of their oxygen functions. In the course of polyketide biosynthesis, highly reactive poly-β-keto intermediates are formed, which often undergo cyclization to six-membered aromatic or 2-pyrone rings. Many polyketides are phenolics like the phenylpropanoids, but the two groups can be distinguished by the substitution pattern of the aromatic ring. While polyketides usually contain oxygen functions on alternate carbons (meta position), phenolics derived from the phenylpropanoid pathway show an ortho oxygenation pattern. Many polyketides are glycosylated and may carry acyl substitutents on the sugar unit.

Polyketides occuring in plants are not always exclusively synthesized from acetate units, but often are of mixed biosynthetic origin. Phenylpropanoid or terpenoid building blocks or sometimes both can be connected with the acetate-derived backbone. In addition, parts of the carbon skeleton can be derived from fatty acids or amino acids. This mixed assembly principle results in a plethora of structurally diverse compounds. Polyketide alkaloids obtained when nitrogen or nitrogen-containing precursors are incorporated into the polyketide backbone will also be discussed.

22 Polyketides Derived Exclusively from Acetate Units

Naphthoquinones of polyketide origin occur in a few taxonomically related families of the order Caryophyllales (Heubl et al., 2006), e.g., the Droseraceae, Nepenthaceae, Plumbaginaceae, and Polygonaceae, but also in the unrelated genus Diospyros (Ebenaceae) (Thomson, 1987). These compounds are built from six acetate units, and one carbon is lost in the course ot their biosynthesis, thus yielding an eleven carbon skeleton with two six-membered rings (Fig. 19). Plants that accumulate naphthoquinones often also contain naphthohydroquinone glycosides and dimeric naphthoquinones. Naphthoquinones, e.g., plumbagin and droserone, are strongly colored and lipophilic substances. Plumbagin is accumulated predominantly in roots and acts as an allelopathic compound. It has also antifeedant effects on insects (Tokunaga et al., 2004) and antimicrobial properties (Didry et al., 1994). Due to their structural similarity to ubiquinone, naphthoquinones may interfere with mitochondrial electron transport.

Structurally related to the naphthoquinones are the anthraquinones, which originate from eight acetate units and are composed of three six-membered rings. As in the case of the naphthoquinones, one of the sixteen carbons is lost by decarboxylation. Anthrones are reduced anthraquinones and their biosynthetic precursors. Dimeric anthrones are called dianthrones. All three groups of acetate-derived anthranoids in plants have two hydroxy groups at C-1 and C-8, a third hydroxy goup can occur at C-3. They are conjugated with sugar, mostly glucose, as O- and C-glycosides (Fig. 20). The presence of a carbonyl group in conjugation with an aryl is a strong chromophore, and consequently, anthranoids show yellow, orange or red pigmentation. In contrast to naphthoquinones of polyketide origin, anthranoids occur in several unrelated plant families, e.g., the eudicot Fabaceae (Cassia), Rhamnaceae (Rhamnus), Polygonaceae (Rheum), and the monocot Asphodelaceae (Aloe). Anthranoids have antibacterial and antifungal properties (Srinivas et al., 2007) and are therefore probably used as defense compounds.

Plants containing anthranoids are used as laxatives in case of habitual constipation. After ingestion, anthraquinones and dianthrones are converted to anthrones, the active metabolites, by bacteria of the large intestine. Anthrones stimulate the movement of the large intestine and increase secretion of water and electrolytes into the intestinal lumen. Frequent use of athranoid laxatives can lead to dehydration, depletion of minerals, and reversible pigmentation of the intestinal mucosa (pseudomelanosis coli). Emodin, a 1,3,8-trihydroxy-6-methylanthraquinone, proved to be mutagenic in in vitro assays. However, more recent in vitro studies suggest that it has also anti-tumor activities, e.g., by induction of apoptosis, inhibition of cell cycle and angiogenesis (Srinivas et al., 2007).

Hypericin and pseudohypericin (Fig. 21) are naphthodianthrones and occur in St. John’s wort (Hypericum perforatum, Clusiaceae). These dark-red compounds are accumulated in glands on the margin of H. perforatum leaves and petals. It was assumed for a long time that they represent the antidepressant principle in extracts of St. John’s wort. Recently, however, it became evident that the prenylated acylphloroglucinols hyperforin and adhyperforin are responsible for most of the pharmacological effects.

Anthraquinones and naphthoquinones are not exclusively formed via the polyketide biosynthetic route. They can also be derived from the shikimate pathway, e.g., the allelopathic naphthoquinone juglone from the walnut tree (Juglans regia) and the anthraquinone alizarin from madder root (Rubia tinctorium), which was used as purple dye.

23 Polyketides with Phenylpropanoid Moieties

In plants, phenylpropanoid and shikimate derived compounds can be combined with one to three C₂ units derived from malonyl-CoA to yield polyketides of various structures. The largest group of these compounds are the flavonoids with more than 6,000 known compounds (Harborne and Baxter, 1999). Other polyketides of phenylpropanoid origin are less widely distributed, e.g., stilbenes, styrylpyrones, and curcuminoids.

In the structure of flavonoids, the phenylpropanoid C₆-C₃ backbone is extended with three C₂ units that form a second aromatic ring. This basic C₆-C₃-C₆ skeleton of flavonoids can be modified by hydroxylations, methylations, prenylation and, in the case of isoflavonoids, by aryl migration. Flavonoids occur mostly in glycosylated form and are often accumulated in the vacuole. The central intermediates in flavonoid biosynthesis are chalcones, which serve as precursors of all other subgroups (Fig. 22). Flavones, flavonols, flavan-3,4-diols (leucoanthocyanidins), anthocyanins, and proanthocyanidins (polymerized flavan-3-ols, condensed tannins) occur nearly ubiquitously in higher plants. Other subgroups of flavonoids are restricted to certain taxa. Isoflavonoids are produced mainly in leguminous plants (Fabaceae). Aurones are yellow pigments with widespread occurrence, e.g., in snapdragon (Antirrhinum majus), dahlia (Dahlia variabilis), and tickseed (Coreopsis species). Flavan-4-ols or 3-deoxyanthocyanidins are precursors of the phlobaphene polymers, which are red pigments and occur in some Poaceae (Sorghum bicolor, Zea mays) and gloxinia (Sinningia cardinalis) (Winkel-Shirley, 2001).

Flavonoids fulfill several physiological functions in plants. Anthocyanins serve as pigments to attract pollinators and seed dispersers. They are responsible for the red, pink, purple, and blue coloration of many flowers, fruits, and leaves. Different hues and shades are achieved by glycosylation and acylation as well as by complexation with flavones or metal ions and by variation of vacuolar pH. Flavonoids have two absorption maxima in the ultraviolet (UV) range and therefore protect plant tissue from damage by UV radiation (Harborne and Williams, 2000). Anthocyanins absorb also light in the visible range and may provide protection for chlorophyll in senescing leaves from photooxidative damage (Feild et al., 2001). In addition, flavonoids serve as radical scavengers, signaling molecules in symbiotic relationships with rhizobia, and as defense compounds (Dixon and Paiva, 1995). They are important for male fertility (Mo et al., 1992) and modulate the transport of the phytohormone indole-3-acetic acid (Peer and Murphy, 2007). Many naturally occuring flavonoids carry one or two prenyl moieties. This modification renders them more lipophilic than other flavonoids, and consequently, they show higher affinities to biological membranes and often possess antibacterial and antifungal properties (Botta et al., 2005). These phytochemicals are of limited distribution in the plant kingdom and occur in several unrelated families, e.g., in the Fabaceae, Moraceae, Asteraceae, and Rutaceae. While prenylated isoflavonoids of the Fabaceae are phytoalexins and produced upon fungal attack or elicitation, other prenylated flavonoids are accumulated constitutively (Barron and Ibrahim, 1996).

Flavonoids are part of the human diet, and high levels occur in fruits, vegetables, wine, tea, and cocoa. It is suggested that dietary intake of flavonoids has beneficial health effects due to their antioxidant and radical-scavenging properties (Heim et al., 2002). By inhibiting the oxidation of low density lipoprotein (LDL), flavonoids may prevent coronary heart disease. This mechanism has been postulated for the cardio-protective effect of red wine polyphenolics including resveratrol. Two prenylflavonoids from hops (Humulus lupulus) with interesting bioactivities are 8-prenylnaringenin, the strongest phytoestrogen known so far, and the promising cancer chemopreventive agent xanthohumol (Stevens and Page, 2004). Xanthohumol in vitro inhibits phase I enzymes that activate procarcinogens and induces detoxifying phase II enzymes. Moreover, it has radical scavenging activities and inhibits cyclooxygenases 1 and 2, which participate in the biosynthesis of prostaglandins, inflammation mediators that promote carcinogenesis (Gerhäuser et al., 2002). Like 8-prenylnaringenin, many isoflavonoids are phytoestrogens, though much weaker. Food rich in isoflavonoids, especially soy products, may be beneficial for the chemoprevention of hormone-related breast cancer if consumed during adolescence. However, intake of purified genistein, the major isoflavonoid in soy together with daidzein, cannot be regarded as safe, because it increases breast cancer cell growth in animal models (Duffy et al., 2007). A more promising chemo-preventive agent against cancer is (-)-epigallocatechin 3-gallate, the most abundant polyphenol in green tea (Nagle et al., 2006). Various mechanisms are discussed, e.g., induction of apoptosis, cell cycle arrest, inhibition of angiogenesis.

Stilbenes originate from the same biosynthetic precursors as flavonoids, but have a different structure, since the polyketide portion undergoes a different type of cyclization including loss of one carbon by decarboxylation. Stilbenes occur in several unrelated plants such as peanut (Arachis hypogaea), grapevine (Vitis vinifera), rhubarb (Rheum), false hellebores (Veratrum) and pine (Pinus) species. These compounds have antifungal properties. They are induced upon stress, injury, and fungal infection and can therefore be classified as phytoalexins. Stilbene production can be conferred to a plant by transformation with a single gene, stilbene synthase. Several transgenic plants producing stilbenes or stilbene glucosides were described, and some showed enhanced resistance against fungal pathogens (Hain et al., 1993; Thomzik et al., 1997; Zhu et al., 2004).

Resveratrol (Fig. 23), a stilbene found in many food sources, e.g., peanuts and red wine, is assumed to have multiple benefits on human health. Most attention has been received by the so-called “French paradox”, the low occurrence of cardiovacular disease in populations living on a diet high in saturated fats, but consuming red wine. The protective effect of red wine is attributed to its proanthocyanidin and resveratrol contents. Possible mechanisms disscussed are the inhibition of oxidation of LDL cholesterol and platelet aggregation. Resveratrol may also increase longevity by activation of sirtuins, NAD⁺-dependent protein deacetylases involved in aging, which respond to oxidative stress and are induced by a low-calory diet. Resveratrol mimics the effects of a low-calory diet and extends the lifespans of baker’s yeast (Saccharomyces cerevisiae), fruit flies (Drosophila melanogaster), and roundworms (Caenorhabditis elegans) (Howitz et al., 2003; Wood et al., 2004). In addition, resveratrol increases the survival of mice fed on a high-calory diet (Baur et al., 2006). Whether similar beneficial effects can be reproduced in humans will depend on the pharmacokinetics and long-term toxicity of resveratrol in humans.

In styrylpyrones, the phenylpropanoid is extended by two C₂ units derived from malonyl-CoA, and a lactone heterocycle is formed that contains four carbons of polyketide origin and one carbon of the phenylpropanoid side chain. These natural products occur, e.g., in horsetail (Equisetum) and kava (Piper methysticum). Kava grows on the Pacific islands of Melanesia, Micronesia, and Polynesia, and its roots and rhizomes were used to prepare an intoxicating drink named “Kava-Kava” (Briskin, 2000). An extract from the rhizomes of kava is used as medication against anxiety and tension, the styrylpyrones, also called kavapyrones, being the active ingredients (Fig. 23). Kavapyrones interact with the gamma-aminobutyric acid (GABA) receptor (Boonen and Häberlein, 1998), which mediates mainly inhibitory effects in vertebrates. Due to the liver toxicity of kava preparations, this phytomedicine was banned from the European market.

Polyketides with one or two phenylpropanoid moieties and only one carbon derived from malonyl-CoA are the raspberry aroma p-hydroxyphenylbutan-2-one, the curcuminoids of turmeric (Curcuma), and phenylphenalenones from Musa and Anigozanthos species (Fig. 23). Curcuminoids and phenylphenalenones contain two phenylpropanoid moieties on both sides of the acetate-derived carbon and are therefore classified as diarylheptanoids. These two groups of natural products are pigments due to their conjugated system of π-electrons. Curcuminoids are widely used as spices and also have antiinflammatory, antioxidative, and anti-cancer properties (Joe et al., 2004).

24 Polyketides with Terpenoid Building Blocks

This group of natural products comprises the prenylated acylphloroglucinols, e.g., bitter acids from the hop plant (Humulus lupulus) and hyperforin from St. John’s wort (Hypericum perforatum), as well as cannabinoids from Indian hemp (Cannabis sativa) (Fig. 24). These compounds are lipophilic due to their terpenoid moiety and are often produced or stored in special glands or glandular trichomes.

Hop bitter acids and hyperforin are both derived from three different building blocks: a branched short-chain CoA ester derived from amino acid metabolism and three C₂ units derived from malonyl-CoA constitute the acyl phloroglucinol core, which carries two to several isopentenyl side chains that originate from terpenoid metabolism (Adam et al., 2002; Drawert and Beier, 1976; Goese et al., 1999; Karppinen et al., 2007).

Hyperforin accumulates in translucent glands of leaves of St. John’s wort (Soelberg et al., 2007) and represents the major antidepressive principle of this plant. It inhibits the re-uptake of the neurotransmitters serotonin, noradrenaline, dopamine, and GABA, thus increasing their concentrations at the synapses of the brain. This is achieved by an unprecedented mechanism. By elevating the intracellular sodium concentration, hyperforin inhibits the sodium-driven proton gradient required for the transport of neurotransmitters from the synaptic gap into the axoplasm of the neuron (Müller, 2003).

Female inflorescences (cones) of hop carry glandular trichomes that contain volatiles derived from terpenes and fatty acids and a resin consisting of the hop bitter acids with humulone (α-resin) and lupulone (β-resin) as lead compounds. Hop cones are an important ingredient for beer production and contribute to its flavor, in particular its bitter taste. In addition, the hop bitter acids act as foam stabilizers and prevent the growth of bacteria due to their antimicrobial properties. Extracts of hop cones are also used as a mild sedative and sleep inducer.

Cannabinoids are derived from hexanoyl-CoA, three molecules of malonyl-CoA and the C₁₀ terpenoid geranyldiphosphate. They occur only in Indian hemp, which belongs to the Cannabaceae family like hop. C. sativa plants accumulate a resin in glandular trichomes that are more abundant on female inflorescences than on male. The glandular resin contains more than sixty cannabinoids, e.g., δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD) (Turner et al., 1980). Cannabis has been used as psychoactive drug since prehistoric times. Its use is nowadays prohibited in most parts of the world, but cultivation of C. sativa plants with low THC contents is permitted for production of fibers and oil-rich seeds in serveral countries, though not in the USA. The dried flowering parts of female hemp plants are termed marihuana, while hashish (Arabic for “grass”) is their concentrated resin. These cannabis preparations are usually smoked, but they can also be ingested orally, e.g., as cakes or cookies. THC, the major psychoactive compound in cannabis, binds to cannabinoid receptors that occur in brain, spinal cord and immune cells. The consumption of cannabis products leads to a feeling of euphoria and relaxation, but repeated use may cause addiction (Dewick, 2002). Nevertheless, THC has also useful medicinal properties, e.g., anti-emetic, analgesic, and appetite-inducing. It is used for the prevention of nausea during radiotherapy and chemotherapy and as treatment of the wasting syndrome in AIDS patients.

25 Polyketide Alkaloids

The most famous compounds of this group are probably the piperidine alkaloids of poison hemlock (Conium maculatum), which were used to execute the Greek philosopher Socrates. While piperidine alkaloids are usually synthesized from the amino acid L-lysine, the carbon skeleton of the piperidine alkaloids in C. maculatum originates from four acetate units (Leete, 1963, 1964). Only the nitrogen is derived from L-alanine by transamination (Roberts, 1971). Hemlock alkaloids are accumulated in all plant parts, however, highest levels are found in unripe fruits (1.6%) (Dewick, 2002). The two major hemlock alkaloids are γ-coniceine and coniine (Fig. 25). Piperidine alkaloids like coniine occur not only in C. maculatum, but also in several Aloe species (Reynolds, 2005). These compounds are neurotoxic and cause paralysis, muscular tremor and death by respiratory paralysis.

Although the carbon skeleton of naphthylisoquinoline alkaloids is much more complex than that of the coniine alkaloids, it is composed of the same building blocks, C₂ units derived from acetyl-CoA and malonyl-CoA. Each part the the naphthylisoquinoline skeleton, naphthalene and isoquinoline moiety, are derived from six acetate units. Nitrogen is incorporated only in the isoquinoline part and most likely derived from amino acid metabolism (Bringmann and Feineis, 2001). Naphthylisoquinoline alkaloids occur only in the plant families Ancistrocladaceae and Dioncophyllaceae that comprise lianas from southeast Asia and Africa. They were shown to possess fungicidal activities and antifeedant properties towards insects, which might relate to their physiological function. Michellamine B, a dimeric naphthylisoquinoline from the liana Ancistrocladus korupensis, was discovered during a screening by the U.S. National Cancer Institute. It showed promising anti-HIV acitivity by inhibiting the viral reverse transcriptase and by blocking the fusion of virus particles with the human cell membrane (McMahon et al., 1995). Other alkaloids of this group, e.g., dioncophylline C (Fig. 25) and ancistrocladinium A and B, have antiplasmodial and antileishmanial properties, respectively (François et al.,1997; Ponte-Sucre et al., 2007).

In contrast to the previous two groups of alkaloids, the nitrogen in the backbone of acridone alkaloids is not acquired by transamination from an amino acid. Instead, the nitrogen and part of the carbon skeleton of acridones originate from N-methylanthraniloyl-CoA, which is derived from the shikimate pathway. In addition, three C₂ units derived from malonyl-CoA are incorporated. The basic acridone skeleton can be modified by prenylation with dimethylallyldiphosphate (DMAPP), which can be followed by the formation of an additional heterocyclic five- or six-membered ring. In plants, acridone alkaloids occur abundantly in the Rutaceae family. Due to their planar aromatic structure, acridones can intercalate DNA. Acronycine (Fig. 25) from Acronychia baueri showed promising anticancer activity, but did not yield convincing results in clinical studies. Its new derivative S23609-2, a benzoacronycine, is a potent DNA-alkylating agent and currently undergoes phase I clinical trials (Léonce et al., 2006).

26 Terpenoids

Terpenoids, also named isoprenoids, are the largest class of natural products in plants and comprise more than 40,000 different structures. They are derived from five-carbon isoprene units, and according to the number of isoprene molecules incorporated, they can be classified into hemiterpenes (C₅), monoterpenes (C₁₀), sesquiterpenes (C₁₅), diterpenes (C₂₀), triterpenes (C₃₀), tetraterpenes (C₄₀), and polyterpenes such as rubber (Dewick, 2002). In plants, terpenoids originate from two different biosynthetic routes: the cytosolic mevalonic acid (MVA) pathway and the plastid-located desoxyxylulose phosphate (DXP) pathway (also called methylerythritol phosphate or MEP pathway). Both biosynthetic routes yield the activated isoprene units dimethylallyl diphosphate (DMAPP) and isopentenyl diphosphate (IPP), which are joined by head-to-tail or tail-to-tail linkage and subsequently can undergo cyclization and other modifications, e.g., oxidations or rearrangements. While hemiterpenes, monoterpenes, diterpenes, and tetraterpenes are derived from the DXP pathway, triterpenes, steroids, and certain sesquiterpenes originate from mevalonic acid (Fig. 26). Although MVA and DXP pathway are located in different compartments, there is an exchange between the two biosynthetic routes, especially from the plastidial to the cytosolic pathway (Laule et al., 2003; Schuhr et al., 2003). This has become particularly evident in the case of several sesquiterpenes, which are synthesized from DMAPP and IPP units provided by the DXP pathway, but not from MVA (Dudareva et al., 2005; Piel et al., 1998).

27 Hemiterpenes

The most abundant true hemiterpene from plants is isoprene (Fig. 27), a volatile compound synthesized from DMAPP. Production and emission of isoprene is distributed very widely in the plant kingdom, and species that synthesize this compound are found among mosses, ferns, gymnosperms, and angiosperms. Many isoprene-emitting species are trees, particularly poplar and aspen, and plants from the humid tropics. Isoprene is emitted into the atmosphere and protects leaves to survive short periods of high temperature. Moreover, it increases the plant’s tolerance towards ozone and reactive oxygen species. (Sharkey et al., 2008).

Hemiterpenes may also act as signaling molecules. Leaves of sagebrush (Artemisia tridentata) emit the highly volatile hemiterpene methacrolein (Fig. 27) in addition to other volatile compounds like hexenal, monoterpenes, and methyljasmonate when the plant is damaged. This is perceived by plants in its close neighborhood and enables them to react faster to a possible attack. A plant that is prepared in this manner, is less likely to be damaged by herbivores (Baldwin et al., 2006).

In addition, C₅ units derived from DMAPP are found in natural products of mixed biosynthetic origin, e.g., prenylated flavonoids, hop bitter acids, and hyperforins.

28 Monoterpenes

Monoterpenes originate from one molecule DMAPP and one molecule IPP that are joined in most cases head-to-tail, yielding all-trans geranyldiphosphate (GPP) (Fig. 28). GPP can be folded into mono-, bi- and tricyclic structures and may undergo other modifications to yield more than 1,000 different monoterpenes. Monoterpenes are lipophilic volatile compounds that occur in defensive resins of conifers, essential oils, and floral scents and contribute to the characteristic flavor or aroma of many plants. Since monoterpenes are volatile, large amounts can only be accumulated in specialized structures. Several plant families, e.g., the Lamiaceae and Asterace, have glandular trichomes with secretory cells that produce terpenes and secrete them into a shared subcuticular storage cavity (Croteau et al., 2005). Similarly, conifers accumulate oleoresin, a complex mixture of mono-, sesqui-, and diterpenes, in resin blisters or ducts, which are covered by a layer of epithelial cells that synthesize and secrete the terpenes into the lumen (Trapp and Croteau, 2001). As in the case of the conifers, many other plants accumulate monoterpenes in mixtures containing the larger sesqui- and diterpenes, rather than monterpenes alone.

The physiological function of monoterpenes is defense, attraction of pollinators, and plant-plant communication (Mahmoud and Croteau, 2002). The role of terpenes in plant-insect-interactions has been particularly well-studied in the example of conifers and the bark beetle. Upon tissue damage by the beetle, oleoresin is secreted from the ducts or produced newly. The volatile turpentine fraction of oleoresin consisting of biologically active mono- and sesquiterpenes, e.g., limonene and pinene, kills the beetles and associated pathogenic fungi. After evaporation of turpentine, the remaining non-volatile rosin fraction consisting of diterpene resin acids solidifies, thus trapping the predators and sealing the wound (Philipps and Croteau, 1999). Despite their toxicity, monoterpenes in oleoresin serve as olfactory signals that help the bark beetles to find their host. Ingested monoterpenes are converted by the beetles to pheromones that either attract more beetles or serve as anti-aggregation signals. In addition, conifer monoterpenes take part in tritrophic interactions and attract insect predators that feed on bark beetles (Trapp and Croteau, 2001).

Many monoterpenes have found application in perfumery, aromatherapy, as cosmetics and insecticides. Menthol, a constituent of essential oils from Mentha species, is the most widely used monoterpene. It is contained in pharmaceuticals, oral health care products, chewing gums, and tobacco products (Croteau et al., 2005). More than 7,000 t of menthol are produced every year either by total synthesis or from the steam-distilled essential oil of cornmint (Mentha arvensis var. piperascens). The cooling sensation stimulated by menthol is caused by excitation of cation channels that serve as thermal receptors (Jordt et al, 2003).

Two monoterpenes with promising anticancer effects are perrillyl alcohol and (+)-(R)-limonene (Mo and Elson, 2004). The two compounds induce apoptosis and suppress translation of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, an enzyme of the MVA pathway. This enzyme is a promising target for anti-tumor compounds, because many proteins involved in cell growth are prenylated, and tumor cells have elevated HMG-CoA reductase levels. Suppression of HMG-CoA reductase is sufficient to decrease terpene biosynthesis in humans, since animals lack the alternative DXP pathway.

Iridoids are monoterpenes with a six-membered oxygen heterocycle annealed to a cycplopentane ring. The hydroxy group of the oxygen containing heterocycle (dihydropyrane) is glucosylated, thus converting the enol-hemiacetal into an acetal (Fig. 29). Cleavage of the cyclopentane ring of the iridoid skeleton yields the secoiridoids, which are biosynthetic building units of the Ipecac alkaloids and the monoterpene indole alkaloids. Iridoids are named after ants of the genus Iridomyrmex that produce these metabolites as defense compounds. In plants, iridoids are chemotaxonomic markers of the genera Plantago (Plantaginaceae), Galium (Rubiaceae), and Scrophularia (Scrophulariaceae) and also occur frequently in the Gentianaceae, Oleaceae, and Verbenaceae (Dinda et al., 2007a, b). Many iridoids have an intense bitter taste and therefore act as feeding deterrents (Seigler, 1998). On the other hand, plants with bitter tasting iridoids, e.g., gentian (Gentiana lutea) with its bitter principle gentiopicroside and amarogentine, are used for the preparation of tonics against anorexia and dyspepsia.

29 Sesquiterpenes

Sesquiterpenes contain three isoprene units and are formed by condensation of DMAPP with two molecules IPP. The central C₁₅ intermediate farnesyldiphosphate (FPP) can be folded into mono-, bi- or tricyclic systems. In general, sesquiterpenes are less volatile than monoterpenes (Dewick, 2002). Initially, it was assumed that all sesquiterpenes are produced via cytosolic MVA pathway. Recent studies, however, revealed that certain sesquiterpenes originate from isoprene units provided by the DXP pathway (Dudareva et al., 2005; Piel et al., 1998) or by both biosynthetic routes (Adam and Zapp, 1998). This can be explained by transport of isoprenoid precursors from the plastids to the cytosol (Bick and Lange, 2003).

Abscisic acid is a sequiterpene phytohormone that is induced by drought and promotes stomatal closure and seed dormancy. Other sesquiterpenes take part in tritrophic plant-herbivore-parasite interactions (reviewed by Dudareva et al., 2006). In maize infested with lepidopteran larvae, the sesquiterpenes (E)-β-farnesene and the (E)-α-bergamotene (Fig. 30) attract the parasitic wasp Cotesia marginiventris (Schnee et al., 2006). Maize roots release (E)-β-caryophyllene (Fig. 30) upon attack of larvae of the beetle Diabrotica virgifera to attract the parasitic nematode Heterorhabditis megidis (Rasmann et al., 2005).

Many sesquiterpenes contain a pentacyclic lactone group and are therefore referred to as sesquiterpene lactones. These compounds occur abundantly in the family Asteraceae. Because of their bitter taste sesquiterpene lactones presumably serve as feeding deterrents of herbivores (Heinrich et al., 1998). Pharmacologically active sesquiterpene lactones often show anti-inflammatory effects due to inhibition of the transcription factor NF-κB that mediates immunological responses and inflammation (Lyß et al., 1998). Sesquiterpenes with such activities occur, for example, in chamomile (Matricaria recutita), one of the most popular medicinal plants. Antimigraine action of some sesquiterpene lactones, e.g., parthenolide from feverfew (Tanacetum parthenium), is mediated by inhibition of platelet aggregation and serotonin secretion (Dewick, 2002). Structural prerequisite for the biological activities of sesquiterpene lactones is an α,β-unsaturated lactone that acts as nucleophile and alkylates proteins, particularly at their thiol groups. On the other hand, alkylation of proteins is the reason for the allergenicity and cytotoxicity of sesquiterpene lactones with an α,β-unsaturated lactone.

Artemisinin is a novel promising agent against malaria. Structurally, it is a tetracyclic sesquiterpene with a six-membered lactone ring and an unusual 1,2,4-trioxane ring (Fig. 30). It occurs in Artemisia annua (qinghao), which has been used for centuries in Traditional Chinese Medicine to treat fevers including malaria. The starting point of the discovery of artemisinin was a request of Ho Chi Minh, the president of North Vietnam, to the Chinese government for a cure against malaria to support his troops in the malaria-infested jungles during the American/Vietnamese war (Hsu, 2006). A screening of plants used in Traditional Chinese medicine revealed the antimalarial activity of an ether extract from A. annua in 1971, and artemisinin (qinghaosu) was isolated as the active principle in the late 1970s. The mode of action of artemisinin is still being investigated. Most likely, it interferes with a sarco-endoplasmic reticulum calcium ATPase (SERCA) of Plasmodium falciparum, but other mechanisms, e.g., alkylation of biological macromolecules or the production of reactive oxygen species are discussed as well (White, 2008). The peroxide bridge is a necessary structural feature required for antimalarial activity. In contrast to quinine, artemisinin kills already young erythrocytic forms of the parasite Plasmodium, thus curing malaria at an early stage. Two semisynthetic analogs, artemether and artesunate, with superior efficiency in comparison to artemisinin were developed and are now used as first-line therapy against malaria in combination with other antimalarial drugs like the quinine analogs mefloquine and lumefantrine. This combination of two drugs tends to prevent resistances of Plasmodium. The success of artemisinin and its analogs has triggered a huge demand that cannot be covered at low cost by extraction of the sesquiterpene from the plant, because A. annua contains only 0.01-1.5% of artemisinin (Covello et al., 2007). Approaches to provide the powerful drug at affordable price for the people in malaria-endemic areas are either breeding of A. annua plants with elevated artemisinin levels or biotechnological production of the artemisinin precursor artemisic acid by cloning the biosynthetic genes from A. annua (Covello et al., 2007) and engineering the pathway into the bacterium Escherichia coli or yeast (Chang et al., 2007; Ro et al., 2006).

30 Diterpenes

Diterpenes originate from the plastdic DXP pathway and are synthesized from DMAPP and three molecules IPP yielding the C₂₀ metabolite geranylgeranyl diphosphate (GGPP). GGPP is the precursor of the lipophilic phytyl side chain of chlorophyll and plastoquinone. Like the smaller terpenes, GGPP can also undergo cyclization and rearrangements to many different structures.

Gibberellins are tetracyclic diterpenes that act as phytohormones and promote shoot elongation, flowering and seed germination (Bishopp et al., 2006). Diterpenes like abietic- and levopimaric acid (Fig. 31) are constitutents of conifer oleoresin and function as defense against herbivores and pathogens. After removal of mono- and sesquiterpenes (turpentine) from oleoresin by distillation, the solid diterpene fraction (rosin) is called colophonium and used on the bows of string instruments. The mono- and sesquiterpene containing distillate is used as oil of turpentine for the thinning of paints and varnishes.

The powerful cytostatic compound paclitaxel (Taxol®) is a diterpene with an N-benzoyl phenylisoserinoyl side chain derived from two molecules phenylalanine (Fig. 31). Paclitaxel was first isolated from the bark of the Pacific yew (Taxus brevifolia) by bioactivity-directed fractionation in 1966, and its structure was elucidated 5 years later (Wani et al., 1971). Its anti-cancer activity is based on a unique mechanism. Paclitaxel binds to microtubules, stabilizes them against depolymerisation and thus blocks cell proliferation (Schiff and Horwitz, 1980). Paclitaxel is used in the therapy of breast, ovarian and lung cancers, cancers of head and neck and Kaposi’s sarcoma. Since paclitaxel occurs only in relatively low amounts in the bark of T. brevifolia (0.01-0.02%) and the trees grow slowly, other sources had to be found to supply enough of the diterpene for industrial production. Today, paclitaxel is obtained either from tissue cultures of various Taxus species or by semisynthesis from baccatin III and 10-deacetylbaccatin III, which can be extracted in sufficient amounts from leaves and twigs of the common yew (T. baccata), a tree that grows much faster than T. brevifolia.

31 Triterpenes and Steroids

Triterpenes are synthesized via the MVA pathway from two molecules of FPP that are joined by tail-to-tail condensation to squalene. Cyclization of its metabolite 2,3-oxidosqualene followed by rearrangements and methyl shifts yields various structures, mostly tetra- or pentacyclic. 2,3-Oxidosqualene is also the precursor of plant steroids. In this case, it is cyclized to the triterpene cycloartenol, which is then converted to the C₂₇ compound cholesterol with the loss of three methyl groups. The oxygen of 2,3-oxidosqualene is usually retained as hydroxy group at C-3 in both triterpenes and steroids.

In contrast to animals, where cholesterol is the major sterol, many plant sterols are methylated or ethylated at C-24 of the side chain, e.g., campesterol and stigmasterol (Fig. 32). These phytosterols are constituents of biomembranes in plants and influence their permeability. Phytosterols inhibit the absorption of cholesterol in animals. Since they are more lipophilic than cholesterol, they are more readily incorporated into the micelles involved in fat digestion. Esters of phytosterols are therefore used as cholesterol-lowering food additives (Dewick, 2002). Brassinosteroids are a group of plant hormones that derive from campesterol. They regulate various biological processes, e.g., stem elongation, leaf expansion, seed germination, and xylem differentiation (Bishopp et al., 2006).

32 Saponins

Triterpene saponins are widely distributed among eudicot plants, for example, in the Araliaceae, Caryophyllaceae, Fabaceae, and Primulaceae families. Monocots, instead, preferably accumulate steroidal saponins, which are abundant in the Agavaceae, Dioscoraceae, and Yuccaceae. Triterpenoid saponins often contain the pentacyclic α-amyrin (ursane), β-amyrin (oleanane) or lupane skeleton or the tetracyclic dammarane backbone as aglycone. This aglycone is linked with one to three carbohydrate chains containing up to six sugar molecules or uronic acids (Dewick, 2002; Hostettmann and Marston, 1995). The first sugar chain is attached to the hydroxy group at C-3 of the triterpene backbone. If two or more carbohydrate chains are present, they are usually connected with hydroxy or carboxy groups at C-28 or C-30.

Steroid saponins can be classified into two groups, spirostanols and furostanols. In furostanols, the side chain of cholesterol is used to form a tetrahydrofuran ring, and the hydroxy group at C-26 is glycosylated. Upon cleavage of this sugar moiety, a second oxygen-containing heterocycle is formed, thus yielding a spirostanol (Fig. 33). Steroidal glycoalkaloids have the same structure like spirostanol saponins, except that the oxygen in the six-membered heterocycle of the spiro function is replaced by nitrogen. As in the case of the triterpene saponins, steroidal saponins carry a sugar chain at the C-3 hydroxy group.

The name saponin is derived from the Latin word “sapo”, soap. This refers to the properties of saponins, which consist like soaps of a lipophilic moiety (triterpenoid or steroid aglycone, also called sapogenin) and a hydrophilic moiety (sugars) and produce foam when shaken in aqueous solution. Plants like soapwort (Saponaria officinalis) and soapbark tree (Quillaia saponaria) were therefore used as detergents. Today, extracts of saponin-containing plants or isolated saponins are used in cosmetics, as detergents and as foaming agents in soft drinks (Güçlü-Üstündag and Mazza, 2007). Saponins lyse red blood cells, a process called hemolysis, because they complex sterols of the plasma membrane and thus increase membrane permeability. This membrane-permeabilizing effect is also responsible for the antimicrobial and antifungal activities of saponins and their function as defence compounds in plants. In general, saponins with only one sugar chain (monodesmosides) show stronger hemolytic and antifungal effects than saponins with two oligosaccharide chains (bisdesmosides). Like cyanogenic glucosides or glucosinolates, bisdesmosidic saponins can be thought of as prodrugs that are cleaved in case of wounding by a specific hydrolase normally located in a different compartment and converted into active defence compounds (Osbourn, 1996). However, one sugar chain is required for the biological activity of saponins, whereas other natural products usually lose their activity when glycosylated.

Taken orally, saponins are not toxic because they are poorly absorbed and the sugar chain important for their hemolytic properties is hydrolyzed. In contrast, saponins are toxic to fish, since they damage the membranes of the gills (Hostettmann and Marston, 1995). Plant material rich in saponins has therefore been used to poison and stupefy fish. The fish can then be caught without difficulty and are not toxic to humans.

Most saponins have a bitter taste, but some sweet saponins are known as well. Glycyrrhizic acid from licorice root (Glycyrrhiza glabra), a β-amyrine type triterpene linked to two molecules of glucuronic acid (Fig. 33), is 50 times sweeter than sucrose (table sugar). Licorice extracts are used to prepare candies (licorice) and as a sweetener. They are also used as mild expectorant and as anti-inflammatory agent. The anti-inflammatory effect is caused by inhibition of an enzyme that inactivates cortisol. On the other hand, this may also lead to side effects such as sodium retention, excretion of potassium, water retention and increased blood pressure.

The roots of ginseng (Panax ginseng) have been used in the traditional medicine of Korea, China and Japan for several thousand years. It is used as adaptogen to help the body to cope with stress, to improve performance and during convalescence (Radad et al., 2006). Active ingredients are saponins, mainly of the dammarane type, containing two or three sugar side chains (Fig. 33) (Dewick, 2002). The ginseng aglycones protopanaxadiol and protopanaxatriol show promising anticancer activities (Güçlü-Üstündag and Mazza, 2007), and a preparation containing ginseng aglycones has been given conditional approval in China for the therapy of various tumors as single agent or in combination with paclitaxel.

The triterpene sapogenins betulinic acid, oleanolic acid and ursolic acid show cytotoxic and anti-inflammatory effects, and based on their structures novel chemopreventive and anticancer agents are being developed (Liby et al., 2007). A derivative of betulinic acid, bevirimat, is the first member of a new class of anti HIV therapeutics, maturase inhibitors. These compounds inhibit the processing of the HIV Gag protein, the precursor of the capsid, and lead to defective and non-infectious virus particles (Li et al., 2003).

33 Tetraterpenes

Tetraterpenes comprise only one group of compounds, the carotenoids. They are synthesized from two molecules GGPP by tail-to-tail addition. Double bonds are inserted to yield an extended conjugated system with all-trans configuration that is responsible for the yellow, orange and red color of the carotenoids. Either one or both ends of the tetraterpene chain are cyclized to a six-membered ring. Carotenoids with hydroxy or epoxy functions are classified as xanthophylls (Dewick, 2002).

Carotenoids fulfill important physiological functions in plants, since they are part of the light harvesting complex and act as accessory pigments of chlorophyll. In addition, they quench triplet chlorophyll and singlet oxygen in case of excess light energy and thus protect the plant from photo-oxidative damage. As pigments of flowers and fruits, carotenoids attract pollinators and seed dispersers (Howitt and Pogson, 2006).

Carotenoids are essential for human health. α-carotene, β-carotene (Fig. 34), and β-cryptoxanthine are precursors of vitamin A. They are taken up with food, cleaved in the intestinal mucosa and converted in the liver to vitamin A, which serves as pigment of the light receptors of human eyes. To overcome vitamin A deficiency in areas with malnutrition, a transgenic rice termed, golden rice “was developed that expresses high levels of carotenoid biosynthetic enzymes in the endosperm and accumulates elevated levels of carotenoids (Ye et al., 2000). Due to their anti-oxidant and radical scavenging properties, a diet with fruits and vegetables rich in carotenoids is assumed to decrease the risk of cardiovascular disease or cancer. However, the intake of carotenoids as supplement probably has no health promoting effects (Riccioni et al., 2007; U.S. Preventive Service Task Force, 2003).

References

Adam P, Arigoni D, Bacher A, Eisenreich W (2002) Biosynthesis of hyperforin in Hypericum perforatum. J Med Chem 45:4786–4793
PubMed CAS Google Scholar
Adam KP, Zapp J (1998) Biosynthesis of the isoprene units of chamomile sesquiterpenes. Phytochemistry 48:953–959
CAS Google Scholar
Adlercreutz H (2007) Lignans and human health. Crit Rev Clin Lab Sci 44:483–525
PubMed CAS Google Scholar
Amna T, Puri SC, Verma V, Sharma JP, Khajuria RK, Musarrat J, Spiteller M, Qazi GN (2006) Bioreactor studies on the endophytic fungus Entrophospora infrequens for the production of an anticancer alkaloid camptothecin. Can J Microbiol 52:189-196
PubMed Google Scholar
Ascherio A, Weisskopf MG, O’Reilly EJ, McCullough ML, Calle EE, Rodriguez C, Thun MJ (2004) Coffee consumption, gender, and Parkinson’s disease mortality in the cancer prevention study II cohort: the modifying effects of estrogen. Am J Epidemiol 160:977-984
PubMed Google Scholar
Ashihara H, Suzuki T (2004) Distribution and biosynthesis of caffeine in plants. Front Biosci 9:1864–1876
PubMed CAS Google Scholar
Ashihara H, Crozier A (2001) Caffeine: a well known but little mentioned compound in plant science. Trends Plant Sci 6:407–413
PubMed CAS Google Scholar
Askitopoulou H, Ramoutsaki IA, Konsolaki E (2000) Analgesia and anesthesia: etymology and literary history of related Greek words. Anesth Analg 91:486–91
PubMed CAS Google Scholar
Atkinson J, Morand P, Arnason JT, Niemeyer HM, Bravo HR (1991) Analogs of the cyclic hydroxamic acid 2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3-one (DIMBOA): decomposition to benzoxazolinones and reaction with beta-mercaptoethanol. J Org Chem 56:1788–1800
CAS Google Scholar
Aziz E, Nathan B, McKeever J (2000) Anesthetic and analgesic practices in Avicenna’s Canon of Medicine. Am J Chin Med 28:147–151
PubMed CAS Google Scholar
Baldwin IT, Halitschke R, Paschold A, von Dahl CC, Preston CA (2006) Volatile signaling in plant-plant interactions: “talking trees” in the genomics era. Science 311:812–815
PubMed CAS Google Scholar
Barron D, Ibrahim RK (1996) Isoprenylated flavonoids - a survey. Phytochemistry 43:921–982
CAS Google Scholar
Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337–342
PubMed CAS Google Scholar
Benowitz NL (1990) Clinical pharmacology of caffeine. Annu Rev Med 41:277–288
PubMed CAS Google Scholar
Biastoff S, Dräger B (2007) Calystegines. In: Cordell GA (ed) The Alkaloids, vol 64. Academic, New York
Google Scholar
Bick JA, Lange BM (2003) Metabolic cross talk between cytosolic and plastidial pathways of isoprenoid biosynthesis: Unidirectional transport of intermediates across the chloroplast envelope membrane. Arch Biochem Biophys 415:146–154
PubMed CAS Google Scholar
Bishopp A, Mähönen AP, Helariutta Y (2006) Signs of change: hormone receptors that regulate plant development. Development 133:1857–1869
PubMed CAS Google Scholar
Boerjan W, Ralph J, Baucher M (2003) Lignin biosynthesis. Annu Rev Plant Biol 54:519–546
PubMed CAS Google Scholar
Boonen G, Häberlein H (1998) Influence of genuine kavapyrone enantiomers on the GABA-A binding site. Planta Med 64:504–506
PubMed CAS Google Scholar
Booth M (1998) Opium: a history. MacMillan, New York
Google Scholar
Botta B, Vitali A, Menendez P, Misiti D, Delle Monache G (2005) Prenylated flavonoids: pharmacology and biotechnology. Curr Med Chem 12:717–739
PubMed Google Scholar
Bravo HR, Lazo W (1993) Antimicrobial activity of cereal hydroxamic acids and related compounds. Phytochemistry 33: 569–591
CAS Google Scholar
Bravo HR, Lazo W (1996) Antialgal and antifungal activity of natural hydroxamic acids and related compounds. J Agric Food Chem 44:1569–1571
CAS Google Scholar
Bringmann G, Feineis D (2001) Stress-related polyketide metabolism of Dioncophyllaceae and Ancistrocladaceae. J Exp Bot 52:2015–2022
PubMed CAS Google Scholar
Briskin DP (2000) Medicinal Plants and phytomedicines. Linking plant biochemistry and physiology to human health. Plant Phys 124:507–514
CAS Google Scholar
Bruce-Chwatt LJ (1988) Cinchona and its alkaloids: 350 years. N Y State J Med 88:318–322
PubMed CAS Google Scholar
Chang MCY, Eachus RA, Trieu W, Ro DK, Keasling JD (2007) Engineering Escherichia coli for production of functionalized terpenoids using plant P450s. Nat Chem Biol 3:274–277
PubMed CAS Google Scholar
Chou AC, Chevli R, Fitch CD (1980) Ferriprotoporphyrin IX fulfils the criteria for identification as the chloroquine receptor of malaria parasites. Biochemistry 19:1543-1549
PubMed Google Scholar
Covello PS, Teoh KH, Polichuk DR, Reed DW, Nowak G (2007) Functional genomics and the biosynthesis of artemisinin. Phytochemistry 68:1864-1871
PubMed Google Scholar
Croteau RB, Davis EM, Ringer KL, Wildung MR (2005) (-)-Menthol biosynthesis and molecular genetics. Naturwissenschaften 92:562–577
PubMed CAS Google Scholar
Davin LB, Lewis NG (2005) Lignin primary structures and dirigent sites. Curr Opin Biotechnol 16:407–415
PubMed CAS Google Scholar
Dewick PM (2002) Medicinal natural products: a biosynthetic approach, 2nd edn. Wiley, Chichester
Google Scholar
Didry N, Dubreuil L, Pinkas M (1994) Activity of anthraquinonic and naphthoquinonic compounds on oral bacteria. Pharmazie 49:681–683
PubMed CAS Google Scholar
Dinda B, Debnath S, Harigaya Y (2007a) Naturally occurring iridoids. A review, Part 1. Chem Pharm Bull 55:159–222
CAS Google Scholar
Dinda B, Debnath S, Harigaya Y (2007b) Naturally occurring iridoids. A review, Part 2. Chem Pharm Bull 55:689–728
CAS Google Scholar
Dixon RA, Paiva NL (1995) Stress-induced phenylpropanoid metabolism. Plant Cell 7:1085–1097
PubMed CAS Google Scholar
Dräger B (2004) Chemistry and biology of calystegines. Nat Prod Rep 21:211–223
PubMed Google Scholar
Drawert F, Beier J (1976) Aminosäuren als Vorstufe der Acylseitenkette der Hopfenbitterstoffe. Phytochemistry 15:1693–1694
CAS Google Scholar
Dudareva N, Andersson S, Orlova I, Gatto N, Reichelt M, Rhodes D, Boland W, Gershenzon J (2005) The nonmevalonate pathway supports both monoterpene and sesquiterpene formation in snapdragon flowers. Proc Natl Acad Sci USA 102:933–938
PubMed CAS Google Scholar
Dudareva N, Negre F, Nagegowda DA, Orlova I (2006) Plant volatiles: recent advances and future perspectives. CRC Crit Rev Plant Sci 25:417–440
CAS Google Scholar
Duffy C, Perez K, Partridge A (2007) Implications of phytoestrogen intake for breast cancer. CA Cancer J Clin 57:260–277
PubMed Google Scholar
Dumont P, Ingrassia L, Rouzeau S, Ribaucour F, Thomas S, Roland I, Darro F, Lefranc F, Kiss R (2007) The Amaryllidaceae isocarbostyril narciclasine induces apoptosis by activation of the death receptor and/or mitochondrial pathways in cancer cells but not in normal fibroblasts. Neoplasia 9:766–76
PubMed Google Scholar
Eisner T, Meinwald J (1995) The chemistry of sexual selection. Proc Natl Acad Sci USA 92:50–55
PubMed CAS Google Scholar
Fahey JW, Zalcmann AT, Talalay P (2001) The chemical diversity and distribution of glucosinolates and isothiocyanates among plants. Phytochemistry 56:5–51
CAS Google Scholar
Feild TS, Lee DW, Holbrook NM (2001) Why leaves turn red in autumn. The role of anthocyanins in senescing leaves of red-osier dogwood. Plant Physiol 127:566–574
PubMed CAS Google Scholar
François G, Timperman G, Eling W, Assi LA, Holenz J, Bringmann G (1997) Naphthylisoquinoline alkaloids against malaria: evaluation of the curative potentials of dioncophylline C and dioncopeltine A against Plasmodium berghei in vivo. Antimicrob Agents Chemother 41:2533–2539
PubMed Google Scholar
Frei H, Lüthy J, Brauchli J, Zweifel U, Würgler FE, Schlatter C (1992) Structure/activity relationships of the genotoxic potencies of sixteen pyrrolizidine alkaloids assayed for the induction of somatic mutation and recombination in wing cells of Drosophila melanogaster. Chem Biol Interact 83:1-22
PubMed Google Scholar
Frick S, Kramell R, Schmidt J, Fist AJ, Kutchan TM (2005) Comparative qualitative and quantitative determination of alkaloids in narcotic and condiment Papaver somniferum cultivars. J Nat Prod 68:666–673
PubMed CAS Google Scholar
Friedmann J, Waller GR (1985) Caffeine hazards and their prevention in germinating seeds of coffee (Coffea arabica L.). J Chem Ecol 9:1099–1106
Google Scholar
Fujii T, Ohba M (1998) The ipecac alkaloids and related bases. In: Cordell GA (ed) The alkaloids, vol 51. Academic, New York
Google Scholar
Gates M, Tschudi G (1952) The synthesis of morphine. J Am Chem Soc 74:1109-1110
Google Scholar
Geiger PL, Hesse K (1833) Darstellung des Atropins. Ann Pharm 5:43–81
Google Scholar
Gerhäuser C, Alt A, Heiss E, Gamal-Eldeen A, Klimo K, Knauft J, Neumann I, Scherf HR, Frank N, Bartsch H, Becker H (2002) Cancer chemopreventive activity of xanthohumol, a natural product derived from hop. Mol Cancer Ther 1:959–969
PubMed Google Scholar
Goese M, Kammhuber K, Bacher A, Zenk MH, Eisenreich W (1999) Biosynthesis of bitter acids in hops. A 13C-NMR and 2H-NMR study in the building blocks of humulone. Eur J Biochem 263:447-454
PubMed Google Scholar
Goldmann A, Milat ML, Ducrot PH, Lallemand JY, Maille M, Lepingle A, Charpin I, Tepfer D (1990) Tropane derivatives from Calystegia sepium. Phytochemistry 29:2125-2128
Google Scholar
Griffin WJ, Lin GD (2000) Chemotaxonomy and geographical distribution of tropane alkaloids. Phytochemistry 53:623–637
PubMed CAS Google Scholar
Grombacher AW, Russell WA, Guthrie WD (1989) Resistance to first-generation European corn borer (Lepidoptera: Pyralidae) and DIMBOA concentration in midwhorl leaves of the BS9 maize synthetic. J Kans Entomol Soc 62:103–107
Google Scholar
Güçlü-Üstündag Ö, Mazza G (2007) Saponins: properties, applications and processing. Crit Rev Food Sci Nutr 47:231–258
PubMed Google Scholar
Hain R, Reif HJ, Krause E, Langebartels R, Kindl H, Vornam B, Wiese W, Schmelzer E, Schreier PH, Stöcker RH, Stenzel K (1993) Disease resistance results from foreign phytoalexin expression in a novel plant. Nature 361:153–156
PubMed CAS Google Scholar
Halkier BA, Gershenzon J (2006) Biology and biochemistry of glucosinolates. Ann Rev Plant Biol 57:303–333
CAS Google Scholar
Harborne JB, Baxter H (1999) The handbook of natural flavonoids, vols 1 and 2. Wiley, Chichester
Google Scholar
Harborne JB, Williams CA (2000) Advances in flavonoid research since 1992. Phytochemistry 55:481–504
PubMed CAS Google Scholar
Hartmann T, Ober D (2000) Biosynthesis and metabolism of pyrrolizidine alkaloids in plants and specialized insect herbivores. Top Curr Chem 209:207–243
CAS Google Scholar
Hartmann T, Sander H, Adolph R, Toppel, G (1988) Metabolic links between the biosynthesis of pyrrolizidine alkaloids and polyamines in root cultures of Senecio vulgaris. Planta 175:82–90
CAS Google Scholar
Hasegawa M, Sasaki T, Sadakane K, Tabuchi M, Takeda Y, Kimura M, Fujii Y (2002) Studies for the emetic mechanisms of ipecac syrup (TJN-119) and its active components in ferrets: involvement of 5-hydroxytryptamine receptors. Jpn J Pharmacol 89:113-119
PubMed Google Scholar
Hashimoto Y, Shudo K (1996) Chemistry of biologically active benzoxazinoids. Phytochemistry 43:551–559
PubMed CAS Google Scholar
Hegnauer R (1986) Chemotaxonomie der Pflanzen. Vol 7. Birkhäuser Verlag, Basel
Google Scholar
Heim KE, Tagliaferro AR, Bobilya DJ (2002) Flavonoids antioxidants: chemistry, metabolism and structure-activity relationships. J Nutr Biochem 13:572–584
PubMed CAS Google Scholar
Heinrich M (2004) Snowdrops: the heralds of spring and a modern drug for Alzheimer’s disease. Pharmaceutical J 273:905–906
Google Scholar
Heinrich M, Robles M, West JE, Ortiz de Montellano BR, Rodriguez E (1998) Ethnopharmacology of Mexican Asteraceae (Compositae). Annu Rev Pharmacol Toxicol 38:539–565
PubMed CAS Google Scholar
Heubl G, Bringmann G, Meimberg H (2006) Molecular phylogeny and character evolution of carnivorous plant families in Caryophyllales - revisited. Plant Biol 8:821–830
PubMed CAS Google Scholar
Higdon JV, Delage B, Williams DE, Dashwood RH (2007) Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis. Pharmacol Res 55:224–236
PubMed CAS Google Scholar
Hollingsworth RG, Armstrong JW, Campbell E (2002) Caffeine as a repellent for slugs and snails. Nature 417:915–916
PubMed CAS Google Scholar
Hostettmann KA, Marston A (1995) Saponins. Cambridge University Press, Cambridge
Google Scholar
Howitt CA, Pogson BJ (2006) Carotenoid accumulation and function in seeds and non-green tissues. Plant Cell Environ 29:435–445
PubMed CAS Google Scholar
Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425:191–196
PubMed CAS Google Scholar
Howland R, Mycek MJ, Harvey RA, Champe PC (2005) Lippincott’s Illustrated Reviews: Pharmacology, 3rd edn. Lippincott William & Wilkins, Philadelphia, PA
Google Scholar
Hsiang YH, Hertzberg R, Hecht S, Liu LF (1985) Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem 260:14873–14878
PubMed CAS Google Scholar
Hsiang YH, Lihou MG, Liu LF (1989) Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res 49:5077–5082
PubMed CAS Google Scholar
Hsu E (2006) Reflections on the ‘discovery’ of the antimalarial qinghao. Br J Clin Pharmacol 61:666–670
PubMed Google Scholar
Hutchinson CR, Heckendorf AH, Daddona PE, Hagaman E, Wenkert E (1974) Biosynthesis of camptothecin. I. Definition of the overall pathway assisted by carbon-13 nuclear magnetic resonance analysis. J Am Chem Soc 96:5609-5611
PubMed Google Scholar
Ieven M, van den Berghe DA, Vlietinck AJ (1983) Plant antiviral agents. IV. Influence of lycorine on growth pattern of three animal viruses. Planta Med 49:109–114
CAS Google Scholar
Jin Z (2007) Amaryllidaceae and Sceletium alkaloids. Nat Prod Rep 24:886–905
PubMed CAS Google Scholar
Joe B, Vijaykumar M, Lokesh BR (2004) Biological properties of curcumin - cellular and molecular mechanisms of action. Crit Rev Food Sci Nutri 44:97–111
CAS Google Scholar
Jones DA (1988) Cyanogenesis in animal-plant interactions. Ciba Found Symp 140:151–170
PubMed CAS Google Scholar
Jones DA (1998) Why are so many food plants cyanogenic? Phytochemistry 47:155–162
PubMed CAS Google Scholar
Jordan MA, Thrower D, Wilson L (1991) Mechanism of inhibition of cell proliferation by Vinca alkaloids. Cancer Res 51:2212–2222
PubMed CAS Google Scholar
Jordt SE, McKemy DD, Julius D (2003) Lessons from peppers and peppermint: the molecular logic of thermosensation. Curr Opin Neurobiol 13:487–492
PubMed CAS Google Scholar
Jørgensen K, Bak S, Busk PK, Sørensen C, Olsen CE, Puonti-Kaerlas J, Møller BL (2005) Cassava plants with a depleted cyanogenic glucoside content in leaves and tubers. Distribution of cyanogenic glucosides, their site of synthesis and transport, and blockage of the biosynthesis by RNA interference technology. Plant Phys 139:363–374
Google Scholar
Kalemba D, Kunicka A (2003) Antibacterial and antifungal properties of essential oils. Curr Med Chem 10:813–829
PubMed CAS Google Scholar
Karppinen K, Hokkanen J, Tolonen A, Mattila S, Hohtola A (2007) Biosynthesis of hyperforin and adhyperforin from amino acid precursors in shoot cultures of Hypericum perforatum. Phytochemistry 68:1038–1045
PubMed CAS Google Scholar
Kaufman TS, Rúveda EA (2005) The quest for quinine: those who won the battles and those who won the war. Angew Chem Int Ed 44:854–885
CAS Google Scholar
Klein RM (1987) The green world: an introduction to plants and people. HarperCollins, New York
Google Scholar
Knudsen JT, Tollsten L, Bergström G (1993) Floral scents: a checklist of volatile compounds isolated by head-space techniques. Phytochemistry 33:253–28
CAS Google Scholar
Küenburg B, Czollner L, Fröhlich J, Jordis U (1999) Development of a pilot scale process for the anti-Alzheimer drug (-)-galanthamine using large-scale phenolic oxidative coupling and crystallisation-induced chiral conversion. Org Process Res Dev 3:425–431
Google Scholar
Ladenburg A (1881) Die natürlich vorkommenden mydriatisch wirkenden Alkaloide. Justus Liebigs Ann Chem 206:274–307
Google Scholar
Laule O, Fürholz A, Chang HS, Zhu T, Wang X, Heifetz PB, Gruissem W, Lange M (2003) Crosstalk between cytosolic and plastidial pathways of isoprenoid biosynthesis in Arabidopsis thaliana. Proc Natl Acad Sci USA 100:6866–6871
PubMed CAS Google Scholar
Leete E (1963) The biosynthesis of coniine from four acetate units. J Am Chem Soc 85: 3523–3524
CAS Google Scholar
Leete E (1964) Biosynthesis of the hemlock alkaloids. The incorporation of acetate-1-C14 into coniine and conhydrine. J Am Chem Soc 86:2509–2513
CAS Google Scholar
Léonce S, Kraus-Berthier L, Golsteyn RM, David-Cordonnier MH, Tardy C, Lansiaux A, Poindessous V, Larsen AK, Pierré A (2006) Generation of replication-dependent double-strand breaks by the novel N2-G-alkylator S23906-1. Cancer Res 66:7203–7210
PubMed Google Scholar
Li F, Goila-Gaur R, Salzwedel K, Kilgore NR, Reddick M, Matallana C, Castillo A, Zoumplis D, Martin DE, Orenstein JM, Allaway GP, Freed EO, Wild CT (2003) PA-457: a potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing. Proc Natl Acad Sci USA 100:13555–13560
PubMed CAS Google Scholar
Liby KT, Yore MM, Sporn MB (2007) Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer. Nat Rev Cancer 7:357–5369
PubMed CAS Google Scholar
López-Meyer M, Nessler CL, McKnight TD (1994) Sites of accumulation of the antitumor alkaloid camptothecin in Camptotheca acuminata. Planta Med 60:558–560
PubMed Google Scholar
Lovett R (2005) Coffee: the demon drink? New Scientist, 24 September
Google Scholar
Lyß G, Knorr A, Schmidt TJ, Pahl HL, Merfort I (1998) The anti-inflammatory sesquiterpene lactone helenalin inhibits the transcription factor NF-κB by directly targeting p65. J Biol Chem 273:33508–33516
PubMed Google Scholar
Mahmoud SS, Croteau RB (2002) Strategies fro transgenic manipulation of monoterpene biosynthesis in plants. Trends Plant Sci 7:366–373
PubMed CAS Google Scholar
McLachlan A, Kekre N, McNulty J, Pandey S (2005) Pancratistatin: a natural anti-cancer compound that targets mitochondria specifically in cancer cells to induce apoptosis. Apoptosis 10:619-630
PubMed Google Scholar
McMahon JB, Currens MJ, Gulakowski RJ, Buckheit RW Jr, Lackman-Smith C, Hallock YF, Boyd MR (1995) Michellamine B, a novel plant alkaloid, inhibits human immunodeficiency virus-induced cell killing by at least two distinct mechanisms. Antimicrob Agents Chemother 39:484–488
PubMed CAS Google Scholar
Mein K (1833) Ueber die Darstellung des Atropins in weißen Krystallen. Ann Pharm 6:67–72
Google Scholar
Milder IE, Arts IC, van de Putte B, Venema DP, Hollman PC (2005) Lignan contents of Dutch plant foods: a database including lariciresinol, pinoresinol, secoisolariciresinol and matairesinol. Br J Nutr 93:393-402
PubMed Google Scholar
Mo H, Elson CE (2004) Studies of the isoprenoid-mediated inhibition of mevalonate synthesis applied to cancer chemotherapy and chemoprevention. Exp Biol Med 229:567–585
CAS Google Scholar
Mo Y, Nagel C, Taylor LP (1992) Biochemical complementation of chalcone synthase mutants defines a role for flavonols in functional pollen. Proc Natl Acad Sci USA 89:7213–7217
PubMed CAS Google Scholar
Montllor CB, Bernays EA, Barbehenn RV (1990). Importance of quinolizidine alkaloids in the relationship between larvae of Uresiphita reversalis (Lepidoptera: Pyralidae), and a host plant Cytisus monspessulanus. J Chem Ecol 16:1853–1865
CAS Google Scholar
Müller WE (2003) Current St. John’s wort research from mode of action to clinical efficacy. Pharmacol Res 47:101–109
PubMed Google Scholar
Nagle DG, Ferreira D, Zhou YD (2006) Epigallocatechin-3-gallate (EGCG): chemical and biomedical perspectives. Phytochemistry 67:1849–1855
PubMed CAS Google Scholar
Nandi R, Maiti M (1985) Binding of sanguinarine to deoxyribonucleic acids of differing base composition. Biochem Pharmacol 34:321–324
PubMed CAS Google Scholar
Noble RL (1990) The discovery of the Vinca alkaloids - chemotherapeutic agents against cancer. Biochem Cell Biol 68:1344–1351
PubMed CAS Google Scholar
O’Brien GM, Taylor AJ, Poulter NH (1991) Improved enzymatic assay for cyanogens in fresh and processed cassava. J Sci Food Agric 56:277–289
Google Scholar
O’Connor SE, Maresh JJ (2006) Chemistry and biology of monoterpene indole alkaloid biosynthesis. Nat Prod Rep 23:532–547
PubMed Google Scholar
Osbourn A (1996) Saponins and plant defence - a soap story. Trends Plant Sci 1:4–9
Google Scholar
Peer WA, Murphy AS (2007) Flavonoids and auxin transport: modulators or regulators? Trends Plant Sci 12:556–563
PubMed CAS Google Scholar
Pérez FJ, Niemeyer HM (1989) Reaction of DIMBOA with amines. Phytochemistry 28:1831–1834
Google Scholar
Phillips MACroteau, (1999) Resin-based defenses in conifers. Trends Plant Sci 4:184–190
PubMed Google Scholar
Pichersky E, Dudareva N (2007) Scent engineering: toward the goal of controlling how flowers smell. Trends Biotechnol 25:105–110
PubMed CAS Google Scholar
Piel J, Donath J, Bandemer K, Boland W (1998) Mevalonate-independent biosynthesis of terpenoid volatiles in plants: induced and constitutive emission of volatiles. Angew Chem Int Ed 37: 2478–2481
CAS Google Scholar
Plowman T, Rivier L (1983) Cocaine and cinnamoylcocaine content of Erythroxylum species. Ann Bot 51:641–659
CAS Google Scholar
Ponte-Sucre A, Faber JH, Gulder T, Kajahn I, Pedersen SE, Schultheis M, Bringmann G, Moll H (2007) Activities of naphthylisoquinoline alkaloids and synthetic analogs against Leishmania major. Antimicrob Agents Chemother 51:188–194
PubMed CAS Google Scholar
Puri SC, Verma V, Amna T, Qazi GN, Spiteller M (2005) An endophytic fungus from Nothapodytes foetida that produces camptothecin. J Nat Prod 68:1717–1719
PubMed CAS Google Scholar
Radad K, Gille G, Liu L, Rausch WD (2006) Use of ginseng in medicine with emphasis on neurodegenerative disorders. J Pharmacol Sci 100:175–186
PubMed CAS Google Scholar
Rasmann S, Kollner TG, Degenhardt J, Hiltpold I, Toepfer S, Kuhlmann U. Gershenzon J, Turlings TCJ (2005) Recruitment of entomopathogenic nematodes by insect-damaged maize. Nature 434:732–737
PubMed CAS Google Scholar
Ratzka A, Vogel H, Kliebenstein DJ, Mitchell-Olds T, Kroymann J. 2002. Disarming the mustard oil bomb. Proc Natl Acad Sci USA 99:11223–11228
PubMed CAS Google Scholar
Reynolds T (2005) Hemlock alkaloids from Socrates to poison aloes. Phytochemistry 66:1399–1406
PubMed CAS Google Scholar
Riccioni G, Bucciarelli T, Mancini B, Corradi F, Di Ilio C, Mettei PA, D’Orazio N (2007) Antioxidant vitamin supplementation in cardiovascular diseases. Ann Clin Lab Sci 37:89–95
PubMed CAS Google Scholar
Rivier L (1981) Analysis of alkaloids in leaves of cultivated Erthroxylum and characterization of alkaline substances used during coca chewing. J Ethnopharmacol 3:313–335
PubMed CAS Google Scholar
Ro DK, Paradise EM, Quellet M, Fisher KJ, Newman KL, Ndungu JM, Ho KA, Eachus RA, Ham TS, Kirby J, Chang MC, Withers ST, Shiba Y, Sarpong R Keasling JD (2006) Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 440:940-943
PubMed Google Scholar
Roberts MF (1971) The formation of γ-coniceine from 5-ketooctanal by a transaminase of Conium maculatum. Phytochemistry 10:3057–3060
CAS Google Scholar
Röder E (1995) Medicinal plants in Europe containing pyrrolizidine alkaloids. Pharmazie 50:83–98
Google Scholar
Rouhi AM, Washington C, Washington EN (2000) Lignin and lignan biosynthesis. Chem Eng News 78:29–32
Google Scholar
Saleem M, Kim HJ, Ali MS, Lee YS (2005) An update on bioactive plant lignans. Nat Prod Rep 22:696-716
PubMed Google Scholar
Sánchez-Pérez R, Jørgensen K, Olsen CE, Dicenta F, Møller BL (2008) Bitterness in almonds. Plant Physiol 146:1040–1052
PubMed Google Scholar
Sanderson K (2007) Opiates for the masses. Nature 449:268–269
PubMed CAS Google Scholar
Schiff P (2002) Opium and its alkaloids. Am J Pharm Edu 66
Google Scholar
Schiff PB, Horwitz SB (1980) Taxol stabilizes microtubules in mouse fibroblast cells. Proc Natl Acad Sci USA 77:1561–1565
PubMed CAS Google Scholar
Schmidt E (1892) Ueber Scopolamin. Arch Pharm 230:207–231
Google Scholar
Schnee C, Kollner TG, Held M, Turlings TCJ, Gershenzon J, Degenhardt J (2006) The products of a single maize sesquiterpene synthase form a volatile defense signal that attracts natural enemies of maize herbivores. Proc Natl Acad Sci USA 103:1129–1134
PubMed CAS Google Scholar
Schuhr CA, Radykewicz T, Sagner S, Latzel C, Zenk MH, Arigoni D, Bacher A, Rohdich F, Eisenreich W (2003) Quantitative assessment of crosstalk between the two isoprenoid biosynthesis pathways in plants by NMR spectroscopy. Phytochemistry Rev 2:3–16
CAS Google Scholar
Seigler DS (1991) Cyanide and cyanogenic glucosides. In: Rosenthal GA, Berenbaum MR (eds) Herbivores: their interactions with secondary plant metabolites. Academic, San Diego, CA
Google Scholar
Seigler DS (1998) Iridoid monoterpenes. In: Plant secondary metabolism. Kluwer, Dordrecht
Google Scholar
Selmar D (1999) Biosynthesis of cyanogenic glycosides, glucosinolates and non-protein amino acids. In: Wink M (ed) Biochemistry of plant secondary metabolism. Sheffield Acad Press, England
Google Scholar
Selmar D, Lieberei R, Biehl B (1988) Mobilization and utilization of cyanogenic glycosides: the linustatin pathway. Plant Physiol 86:711–716
PubMed CAS Google Scholar
Sharkey TD, Wiberley AE, Donohue AR (2008) Isoprene emission from plants: why and how. Ann Bot (Lond) 101:5–18
CAS Google Scholar
Sheriha GM, Rapoport H (1976) Biosynthesis of Camptotheca acuminata alkaloids. Phytochemistry 15:505–508
CAS Google Scholar
Sicker D, Frey M, Gierl A (2000) Role of natural benzoxazinones in the survival strategy of plants. Int Rev Cytol 198:319–346
PubMed CAS Google Scholar
Sirikantaramas S, Asano T, Sudo H, Yamazaki M, Saito K (2007) Camptothecin: therapeutic potential and biotechnology. Curr Pharm Biotechnol 8:196–202
PubMed CAS Google Scholar
Siritunga D, Sayre R (2007) Transgenic approaches for cyanogen reduction in cassava. AOAC Int. 90:1450–1455
CAS Google Scholar
Soelberg J, Jørgensen LB, Jäger AK (2007) Hyperforin accumulates in the translucent glands of Hypericum perforatum. Ann Bot 99:1097–1100
PubMed CAS Google Scholar
Srinivas G, Babykutty S, Sathiadevan PP, Srinivas P (2007) Molecular mechanism of emodin action: transition from laxative lngredient to an antitumor agent. Med Res Rev 27:591–608
PubMed CAS Google Scholar
Stevens JF, Page JE (2004) Xanthohumol and related prenylflavonoids from hops and beer: to your good health! Phytochemistry 65:1317–1330
PubMed CAS Google Scholar
Stirling IR, Freer IKA, Robins DJ (1997) Pyrrolizidine alkaloid biosynthesis. Incorpora-tion of 2-aminobutanoic acid labelled with 13C or 2H into the senecic acid portion of rosmarinine and senecionine. J Chem Perkin Trans I 5:677–680
Google Scholar
Straub KD, Carver P (1975) Sanguinarine, inhibitor of Na-K dependent ATP’ase. Biochem Biophys Res Commun 62:913–922
PubMed CAS Google Scholar
Sudo H, Yamakawa T, Yamazaki M, Aimi N, Saito K (2002) Bioreactor production of camptothecin by hairy root cultures of Ophiorrhiza pumila. Biotechnol Lett 24:359–363
CAS Google Scholar
Sullivan DJ Jr, Gluzman IY, Russell D G, Goldberg DE (1996) On the molecular mechanism of chloroquine’s antimalarial action. Proc Natl Acad Sci USA 93:11865–11870
PubMed CAS Google Scholar
Sun XF, Sun RC, Fowler P, Baird MS (2005) Extraction and characterization of original lignin and hemicelluloses from wheat straw. J Agric Food Chem 53:860-870
PubMed CAS Google Scholar
Szlávik L, Gyuris A, Minárovits J, Forgo P, Molnár J, Hohmann J (2004) Alkaloids from Leucojum vernum and antiretroviral activity of Amaryllidaceae alkaloids. Planta Med 70:871–873
PubMed Google Scholar
Tattersall DB, Bak S, Jones PR, Olsen CE, Nielsen JK, Hansen ML, Høj PB, Møller BL (2001) Resistance to an herbivore through engineered cyanogenic glucoside synthesis. Science 293:1826–1828
PubMed CAS Google Scholar
Tepfer D, Goldmann A, Pamboukdjian N, Maille M, Lepingle A, Chevalier D, Dénarié J, Rosenberg C (1988) A Plasmid of Rhizobium meliloti 41 encodes catabolism of two compounds from root exudate of Calystegium sepium. J Bacteriol 170:1153–1161
PubMed CAS Google Scholar
Thomson RH (1987) Naturally occurring quinones, vol III, Chapman & Hall, London
Google Scholar
Thomzik JE, Stenzel K, Stöcker R, Schreier PH, Hain R, Stahl DJ (1997) Synthesis of a grapevine phytoalexin in transgenic tomatoes (Lycopersicon esculentum Mill.) conditions resistance against Phytophthora infestans. Physiol Mol Plant Pathol 51:265–278
CAS Google Scholar
Tokunaga T, Takada N, Ueda M (2004) Mechanism of antifeedant activity of plumbagin, a compound concerning the chemical defense in carnivorous plant. Tetrahedron Lett 45:7115–7119
CAS Google Scholar
Trapp S, Croteau R (2001) Defensive resin biosynthesis in conifers. Annu Rev Plant Physiol Plant Mol Biol 52:689–724
PubMed CAS Google Scholar
Turner CE, Elsohly MA, Boeren EG (1980) Constituents of Cannabis sativa L. XVII. A review of the natural constituents. J Nat Prod 43:169–234
CAS Google Scholar
U.S. Preventive Services Task Force (2003) Routine vitamin supplementation to prevent cancer and cardiovascular disease: recommendations and rationale. Ann Intern Med 139:51-55
Google Scholar
Van der Heijden R, Jacobs DI, Snoeijer W, Hallard D, Verpoorte R (2004) The Catharanthus alkaloids: pharmacognosy and biotechnology. Curr Med Chem 11:607–628
PubMed CAS Google Scholar
Vincent RM, López-Meyer M, McKnight TD, Nessler CL (1997) Sustained harvest of camptothecin from the leaves of Camptotheca acuminata. J Nat Prod 60:618–619
PubMed CAS Google Scholar
Wall ME, Wani MC, Cook CE, Palmer KH, McPhail AT, Sim GA (1966) Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata. J Am Chem Soc 88:3888–3890
CAS Google Scholar
Wani MC, Taylor HL, Wall ME, Coggin P, McPhail AT (1971) Plant antitumor agents. VI. Isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc 93:2325–2327
PubMed CAS Google Scholar
Weber S, Eisenreich W, Bacher A, Hartmann T (1998) Pyrrolizidine alkaloids of the lycopsamine type: biosynthesis of trachelanthic acid. Phytochemistry 50:1005–1014
Google Scholar
Weng XL, Bonawitz ND, Chapple C (2008) Emerging strategies of lignin engineering and degradation for cellulosic biofuel production. Curr Opin Biotechnol 19:166–172
PubMed CAS Google Scholar
Werner I, Bacher A, Eisenreich W (1997) Retrobiosynthetic NMR studies with 13C-labeled glucose. Formation of gallic acid in plants and fungi. J Biol Chem 272:25474–25482
PubMed CAS Google Scholar
White NJ (2008) Qinghaosu (Artemisinin): the price of success. Science 320:330–334
PubMed CAS Google Scholar
White SM, Lambe CJT (2003) The pathophysiology of cocaine abuse. J Clin Forensic Med 10:27–39
PubMed Google Scholar
Wink M (2002) Production of quinolizidine alkaloids in in vitro cultures of legumes. In: Nagata, Ebizuka Y (eds) Biotechnology in agriculture and forestry, vol 51: medicinal and aromatic plants XII. Springer, Heidelberg
Google Scholar
Wink M (2003) Allelochemical properties of quinolizidine alkaloids. In: Macías F, Galindo JC, Molinillo JM, Cutler HG (eds) Allelopathy: chemistry and mode of action of allelochemicals. CRC Press, Boca Raton, FL
Google Scholar
Wink M, Witte L (1983) Evidence for a wide-spread occurrence of the genes of quinolizidine alkaloid biosynthesis. FEBS Lett 159:196–200
CAS Google Scholar
Wink M, Witte L (1984) Turnover and transport of quinolizidine alkaloids: diurnal variation of lupanine in the phloem sap, leaves and fruits of Lupinus albus L. Planta 161:519–524
CAS Google Scholar
Wink M, Witte L (1985) Quinolizidine alkaloids as nitrogen source for lupin seedlings and cell suspension cultures. Z Naturforschung 40c:767–775
CAS Google Scholar
Wink M, Witte L (1991) Storage of quinolizidine alkaloids in Macrosiphum albifrons and Aphis genistae (Homoptera: Aphididae). Entomol Gen 15:237–254
Google Scholar
Winkel-Shirley B (2001) Flavonoid biosynthesis. A colorful model for genetics, biochemistry, cell biology, and biotechnology. Plant Physiol 126:485–493
PubMed CAS Google Scholar
Wittstock U, Agerbirk N, Stauber EJ, Olsen CE, Hippler M, Mitchell-Olds T, Gershenzon J, Vogel H (2004) Successful herbivore attack due to metabolic diversion of a plant chemical defense. Proc Natl Acad Sci USA 101:4859–48564
PubMed CAS Google Scholar
Wittstock U, Burow M (2007) Tipping the scales - specifier proteins in glucosinolate hydrolysis. IUBMB Life 59:744–751
PubMed CAS Google Scholar
Wood JG, Rogina B, Lavu S, Howitz KT, Helfand SL, Tatar M, Sinclair DA (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430:686–689
PubMed CAS Google Scholar
Woodward RB, Doering WE (1944) The total synthesis of quinine. J Am Chem Soc 66:849
Google Scholar
World Drug Report of the United Nations (2007)
Google Scholar
Ye X, Al-Babili S, Klöti A, Zhang J, Lucca P, Beyer P, Potrykus I (2000) Engineering the provitamin A (beta-carotene) biosynthetic pathway into (carotenoid-free) rice endosperm. Science 287:303–305
PubMed CAS Google Scholar
Zagrobelny M, Bak S, Møller BL (2008) Cyanogenesis in plants and arthropods. Phytochemistry 69:1457–1468
PubMed CAS Google Scholar
Zenk MH, Jünger M (2007) Evolution and current status of the phytochemistry of nitrogenous compounds. Phytochemistry 68:2757–2772
PubMed CAS Google Scholar
Zhou SF, Xue CC, Yu XQ, Wang G (2007) Metabolic activation of herbal and dietary constituents and its clinical and toxicological implications: an update. Curr Drug Metabol 8:526–553
CAS Google Scholar
Zhu YJ, Agbayani R, Jackson MC, Tang CS, Moore PH (2004) Expression of the grapevine stilbene synthase gene VST1 in papaya provides increased resistance against diseases caused by Phytophthora palmivora. Planta 220:241–250
PubMed CAS Google Scholar

Download references

Author information

Authors and Affiliations

Donald Danforth Plant Science Center, 975 North Warson Road, 63132, St. Louis, MO, USA
Karin Springob & Toni M. Kutchan

Authors

Karin Springob
View author publications
You can also search for this author in PubMed Google Scholar
Toni M. Kutchan
View author publications
You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toni M. Kutchan .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

About this chapter

Cite this chapter

Springob, K., Kutchan, T.M. (2009). Introduction to the Different Classes of Natural Products. In: Osbourn, A., Lanzotti, V. (eds) Plant-derived Natural Products. Springer, New York, NY. https://doi.org/10.1007/978-0-387-85498-4_1

Download citation

DOI: https://doi.org/10.1007/978-0-387-85498-4_1
Published: 01 June 2009
Publisher Name: Springer, New York, NY
Print ISBN: 978-0-387-85497-7
Online ISBN: 978-0-387-85498-4
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)

Publish with us

Policies and ethics