STUDIES ON SECONDARY PLANT METABOLITES AND THEIR...
Transcript of STUDIES ON SECONDARY PLANT METABOLITES AND THEIR...
SECTION 1
A PROLOGUE TO PLANT DERIVED
SECONDARY METABOLITES
1
1. METABOLISM IN PLANTS
The organisms in order to live, grow and reproduce need a source of
energy and provisions of building blocks to construct their own tissues. This
they achieve by transforming and inter converting a vast number of organic
compounds through an integrated network of enzyme mediated and carefully
regulated chemical reactions. The sum of all the chemical reactions occurring
in living cells that provides the organism with matter and energy for its vital
activities is collectively termed as metabolism. Each organized sequence of
chemical and energy transformations by which one molecule is converted to
another is termed a metabolic pathway. Organic molecules involved in these
processes are called metabolites, which include the primary and secondary
metabolites, and they are interconverted during the metabolic processes as the
requirement arises1
.
The reactions involved in the primary metabolism are common to all
organisms and are either catabolic or anabolic.
Catabolism involves reactions in the cell that degrade an organic
matter into smaller or simpler products. Some of the important Catabolic
Pathways are:
1. Glycolysis is the set of reactions where a glucose molecule after
phosphorylation breakdown to a pyruvate molecule. It takes place in
cytoplasm.
2. Krebs or tricarboxylic acid (TCA) cycle takes place in mitochondria
and converts the pyruvate formed during the above process to CO2 and
water. This cycle provides electrons and ATP and also intermediates
for amino acid synthesis.
2
3. Respiration or electron transport chain also takes place in
mitochondria. This is a series of redox reactions for formation of 3
molecules of ATP and water by transferring electrons from
Nicotinamide Adenine Dihydrogenase (NADH) to an electron
acceptor.
Anabolism results in the formation of larger or more complex
molecules from smaller organic moiety. This includes the biosynthesis of the
molecules such as nucleotides, amino acids, hexosamines, fatty acids and
sugars and polymerization reactions which lead to the formation of larger
molecules such as DNA, RNA, proteins, peptidoglycans, lipids,
lipopolysaccharides and glycogen2.
The primary metabolites therefor include the nucleic acids and the
common amino acids and sugars and also the high molecular weight
polymeric materials such as cellulose, lignins and the proteins from which the
cellular structures are formed. In plants, compounds derived from primary
pathways make up the bulk of the plant. Some of the intermediates in the
primary metabolism act as the precursor molecules for a different series of
reaction that give end products which are usually the characteristic of a
particular species. These are the secondary metabolites, the molecules of our
concern, which are biosynthetically restricted to a selection of plants or even
to specific species. These appear to have little influence on the growth and
development of plant3.
Secondary metabolites unlike the primary metabolites are found to be
accumulated in particular tissues at high concentration, some of them being
toxic to the plant themselves if they are mislocalized4. Biosynthetic genes
responsible for the formation of those secondary metabolites may be highly
expressed in such tissues. Translocations of these compounds occur as well,
e.g., biosynthetic genes for nicotine in Nicotiana species are mostly expressed
3
in root tissues where as it is transported to the aerial part and is accumulated
in leaves5.
Fig. 1a Major Pathways of biosynthesis of secondary metabolites6
4
The dividing line between primary and secondary metabolism is
indistinct because many of the intermediates in primary metabolism are also
intermediates in secondary metabolism6. For example, several obscure amino
acids are definitely secondary metabolites, whereas many sterols play an
essential structural role in most organisms and must therefore be considered
as primary metabolites. The overlapping role of many compounds ensures a
close interconnection between primary and secondary metabolism7. A further
view is that the secondary compounds may be a convenient sink, into which
excess carbon and nitrogen can be diverted away from an inactive part of
primary metabolism. The secondary compounds are then degraded and the
stored carbon and nitrogen recycled back into the primary metabolism, when
there is a demand. The balance between the activities of the primary and
secondary metabolism is a dynamic one, which will be largely affected by
growth, tissue differentiation and development of the plant body and also
external pressures3.
5
2. SECONDARY METABOLITES
Plant Secondary Metabolites were frequently considered as
extravaganzas that serve no obvious biological purpose for the plant that
produce them. Their physiological role has not been completely elucidated.
However it is becoming increasingly clear that many plant secondary products
are involved in the interaction of the plant with its environment to cope with
various stress factors and the level of these phytochemicals is largely
determined by environmental conditions8,9
. A wide array of external stimuli
are capable of triggering changes in the plant cell which leads to a cascade of
reactions, ultimately resulting in the formation and accumulation of secondary
metabolites which help the plant to overcome stress factors10,11
. Secondary
metabolites play a significant role in plant survival and are important for plant
interactions with natural enemies including herbivores12,13
, pathogens14
and
competitors15
and with pollinators and seed dispersers16
. Secondary
metabolites are also involved in a number of physiological functions such as
toxic nitrogen storage and transport and UV-protectants17
.
Three basic metabolic processes governed by photosynthesis, i.e.,
nitrogen metabolism, fatty acid metabolism, and carbohydrate metabolism,
are responsible for the synthesis of secondary metabolites which are classified
into several groups based on their chemical structure and biosynthetic routes
providing them.
1.2.1. Phenolic compounds
The term phenolic compound embraces a wide range of plant
substances which possess in common an aromatic ring bearing one or more
hydroxyl groups. Phenolic compounds are generally synthesized via the
shikimate pathway but the polyketide pathway can also provide some
6
phenolics, such asorcinols and quinones. Phenolic compounds derived from
both pathways are quite common, e.g. flavonoids, stilbenes, pyrones and
xanthones. They most frequently occur combined with sugar as glycosides
and are usually located in cell vacuole. They are phenols or phenolic acids,
phenylpropanoids, flavonoids, stylbenes, lignans or xanthenes and tannins as
polymers of polyphenols that are classified into two types, i.e., hydrolyzable
and condensed Tannins. Among these the flavonoids form the largest group
and are brightly coloured compounds which have two benzene rings attached
by a propane unit. Different classes within this group differ by additional
oxygen-containing heterocyclic rings and hydroxyl groups and include the
chalcones, flavones, flavonols, flavanones, anthocyanins and isoflavones.
Anthocyanins impart red and blue pigment to flowers and fruits .The
isoflavonoids are rearranged flavonoids, in which this rearrangement is
brought about by a cytochrome P-450-dependent enzyme. Simple isoflavones
such as daidzein, and coumestans such as coumestrol, have sufficient
estrogenic activity to seriously affect the reproduction of grazing animals and
are known as phytoestrogens18
. Isoflavones exhibit estrogenic,
antiangeogenic, antioxidant and anticancer properties19, 20
. Epidemiological
studies suggest a link between consumption of soy isoflavones and reduced
risks of breast and prostate cancers21
. Isoflavones also possess other health-
promoting activities, such as chemoprevention of osteoporosis, and
prevention of postmenopausal disorders and cardiovascular diseases22, 23
. The
roles of flavonoids in plants also include intracellular and extracellular
signalling, male fertility, and pathogen defence24, 25
. Flavonoids also function
as allelochemicals in plant-plant interaction26
. A prime example of a flavanoid
used in defence is resveratrol, a substance found in the skin of grapes which
inhibits the growth of fungi27
. Resveratrol is also implicated in the prevention
of cancer and cardiovascular diseases in vasoprotection and neuroprotection28-
7
30. The phenylpropenes are important components of many essential oils, e.g.
eugenol in clove oil and anethole and myristicin in nutmeg31
.
Even though the functions of some of the phenolic compounds like
lignans and anthocyanins are well established, the biological role of many
others is not. They are reported to protect the plant against adverse factors
which threaten its survival in an unfavorable environment, such as drought,
infections or physical damage32
. The resistance of plants to UV radiations is
due to the phenolic compounds especially the phenylpropanoids present in
them33
. It is widely recognized that the beneficial influence of many
foodstuffs and beverages including fruits, vegetables, tea, red wine, coffee
and cacao on human health is associated to the antioxidant activity.
Antioxidants are hypothesized to play an important role in disease prevention,
since they may be able to avoid oxidative damage caused by reactive oxidant
species to vital biomolecules such as DNA, lipids and proteins. This type of
oxidative mechanism is accepted to be involved in numerous pathological
processes, such as cardiovascular and neurodegenerative diseases,
inflammation and carcinogenesis34-36
. The phenolic compounds and their
derivatives, due to their activity as antioxidants, play a significant role in the
prevention of diseases by being efficient in protecting cells from oxidative
stress37, 38
. The main mechanism of action of phenolic antioxidants is
considered to be the scavenging of free radicals by hydrogen-atom donation,
although other mechanisms may be involved39
. Thus, the evaluation and
molecular level interpretation of the biological activity of phenolic
compounds is presently the object of intense research. The action phenolic
compounds as neuroprotective40
, fungicidal41
bactericidal42
and their anti-
atherosclerosic effects43
and anticancer activity44, 45
is well documented. The
lignans, secoisolariciresinol and matairesinol from rye or linseed as well as
pinoresinol and lariciresionol are converted by intestinal microorganisms in
humans into the phyto-estrogens enterodiol and enterolactone which are
8
supposed to protect against estrogen-dependent cancers46
. Plant phenolics are
also known to protect food against lipid oxidation, which leads to the
production of undesirable off flavors47
.
Apart from its entire beneficial role these compounds are also
responsible for certain harmful effects. An excessive content of polyphenols,
in particular tannins, may have adverse consequences because it inhibits the
bioavailability of iron48, 49
and thiamine50
and blocks digestive enzymes in the
gastrointestinal tract51
. Phenolic compounds can also limit the bioavailability
of proteins with which they form insoluble complexes in the gastrointestinal
tract52
. Moreover, interactions between tannins and proteins lead to
astringency53
.
1.2.2. Terpenoids
Terpenes are the largest group of phytochemicals and the functional
assortment of chemicals within plants is best demonstrated by them as they
exhibit diverse functions in mediating antagonistic and beneficial interactions
in, and among, organisms54
. The terpenoids are lipid soluble and are located
in the cytoplasm of the cell. Their structures are hypothetically derived from
the isoprene molecule and their carbon skeletons are built up from the union
of two or more of these C5 units joined head to tail. Accordingly they are
classified as hemiterpenes (C5), monoterpenes (C10), sesquiterpenes (C15),
diterpenes (C20), sesterterpenes (C25), triterpenes (C30) and tetraterpenes (C40).
The polymerisation of the isoprene unit gives the rubbers and latex.
Two different biosynthetic pathways produce the main terpene
building block, isopentenyl diphosphate (IPP). The first classical biosynthetic
route is known as the MVA (mevalonic acid) pathway. This takes place in the
cytosol, producing sesquiterpenes55, 56
. The second biosynthetic route to
terpenes is referred to as either the MEP (methylerythriol-4-phosphate) or
9
DOX (1-deoxy-D-xylulose) pathway and takes place in plastid57
. The
evidence indicates that there may be sharing of intermediates across these
pathways, a sort of biosynthetic crosstalk58
.
The volatile essential oils are the mono and sesqui terpenes and are
important as the basis of natural perfumes and also of spices and flavourings
in the food industry. The diterpenes are less volatile and are not considered
essential oils and constitute a component of plant resins because of their
higher boiling point. Gibberellic acid, a plant growth regulator, and taxol are
diterpenes. Some diterpenes that are toxic and are responsible for the
poisonous nature of the plants bearing them.There are examples of diterpenes
that exhibited cytotoxic, antitumor and antimicrobial activities in vitro59
.
Triterpenes are non volatile, high melting and optically active substances and
either are true triterpenes, saponins and sterols or are cardiac glycosides. The
true triterpenoids include the lanostanes, dammaranes, cycloartanol, lupanes,
hopanes etc which occur in various plant parts and cucurbitacins, oleananes
and ursanes occurring in plants of Cucurbitaceae family60
. The limonins and
the cucurbitacins are potent insect steroid hormone antagonists61
. Sterols in
plants generally called the phytosterols are based on the cyclopentane
perhydrophenanthrene ring system. All plant steroids hydroxylated at C3 are
sterols and have profound importance as hormones (androgens such as
testosterone and estrogens such as progesterone), coenzymes and provitamins
in animals. The progesterones are derived semi synthetically from
diosgenin62
. They are also employed in the protection from the predators.
Saponins are glycosides of both triterpenes and sterols and are surface active
agents with soap like properties and can be detected by their ability to cause
foaming and to haemolyse blood cells. The cardiac glycosides have complex
structures and are mostly toxic and are pharmacologically active. The tetra
terpenoids are the carotenoids which are found in all kinds of plants and
10
function as an accessory pigment in photosynthesis and as coloring matters in
fruits and flowers63
.
Terpenes are vital for life in most organisms exerting metabolic control
and mediating inter and intra species interactions, for example, pollination
and defense in plants. Aside from the facts that plants manufacture these
compounds in response to herbivory or stress factors, it has also been shown
that flowers can emit terpenoids to attract pollinating insects and even attract
beneficial mites, which feed on herbivorous insects64
. Kessler and Baldwin65
have reported that herbivorous insects can cause the release of terpenes from
plants and also induce the release of signals that attract predatory species.
Cheng and coworkers66
have reported that terpenes may act as chemical
messengers influencing the expression of genes involved in plant defensive
functions or influence gene expression of neighboring plants. Many terpenes
are reported to act as toxins, growth inhibitors or deterrents to
microorganisms and animals67
.
1.2.3. Organic Acids, Polyketides and Sulphur containing compounds
Plants accumulate organic acids like citric acid, succinic acid, acetic
acid and tartaric acid in their cell vacuole leading to their acidity. Many of the
acids are important to the plant in their primary metabolic pathways. Majority
are non volatile, water soluble, colourless liquids or low melting solids68
.
The polyketides constitute the compounds derived from poly-β-keto
chains and include fatty acids, polyacetylenes, prostaglandins, macrolide
antibiotics and many aromatic compounds like anthraquinones and
tetracyclins. The organic acids and the polyketides are built via the acetate
pathway69
.
Secondary metabolites containing sulphur are rather unusual in plant
and are biosynthesized from sulphur bearing amino acids. They are involved
11
in several different types of chemical defenses; including constitutive,
induced and activated defenses in a broad range of higher plant species as
well as mosses and algae70-72
. They are volatile and carry an acrid taste or an
obnoxious smell. The flavours of mustard, garlic, onion and radish are due to
the sulphur containing components present in them73
.
Among the sulfur-containing secondary metabolites, two groups of
compounds are involved in so-called activated plant defense systems, the
glucosinolates and the alliins. In the intact plant tissue, these compounds,
which are relatively physiologically inert by themselves, are spatially
separated from their hydrolyzing enzymes, the myrosinases and alliinases,
respectively. When the tissue is damaged, for example upon herbivore attack,
the parent compounds are converted to biologically active products by the
action of the hydrolyzing enzymes74,75
. Besides their role in plant defense,
many studies on both glucosinolates and alliins have also been motivated by
the health-promoting effects of these compounds in the human diet. Some
examples are camalexin and related compounds from the Brassicaceae, the
glucosinolates from the Brassicales, the alliines from the Alliaceae, and the
thiophenes from the Asteraceae.
1.2.4. Nitrogen Compounds
Nitrogen containing compounds include amines, alkaloids, cyanogenic
glycosides, indoles, purins, pyrimidines, cytokinins, chlorophylls. They are
mainly associated with the protection of plant from predators.
Simple bases, such as methylamine, trimethylamine and other straight-
chain alkylamines and compounds such as betaines, choline and muscarine
are synthesized from amino acids and categorized as biological amines or
protoalkaloids. As in alkaloids, their nitrogen is not involved in a heterocycle
system. The polyamines, putrescine, spermine, spermidine and the
12
phenylalkylamines, such as β-phenylethylamine, dopamine, ephedrine,
mescaline and tryptamine belong to this class of compounds. An exception to
the above definition is the widely distributed vitamin B1 (thiamine) which
contains nitrogen in heterocycle and has physiological activity76
.
Cytokinins have been correlated to enhanced pathogenic resistance in
plants77,78
. The pain relieving and narcotic properties of opium are known
from ancient times and galanthamine has its use in the treatment of
Alzheimer’s disease.
Alkaloids are a structurally diverse class of nitrogen-containing
compounds, which often possess a strong physiological activity and, over the
centuries, have found many clinical applications. They are regarded as reserve
materials for protein synthesis, as protective substances discouraging animal
or insect attacks, as plant stimulants or regulators or simply as detoxication
products. They occupy an important position in applied chemistry and play an
indispensable role in medicinal chemistry79
. More than 12,000 alkaloids have
been identified in the plant kingdom80
. They occur naturally not only in plants
but also in microorganisms, marine organisms, and animals. Many kinds of
alkaloids with extraordinary structures and significant biological activities
have been isolated from marine organisms81, 82
. In plants, alkaloids generally
exist as salts of organic acids like acetic, oxalic, citric, malic, lactic, tartaric,
tannic and other acids. Some weak basic alkaloids (such as nicotine) occur
freely in nature. A few alkaloids also occur as glycosides of sugar such as
glucose, rhamnose and galactose, e.g. alkaloids of the solanum group
(solanine), as amides (piperine), and as esters (atropine, cocaine) of organic
acids83,84
. They may be present systematically in whole plants, or they may be
accumulated in large amounts in specific organs like roots, stem bark and
seeds. The alkaloids may also be the end product of detoxification reactions
13
and are capable of supplying nitrogen and other necessary fragments to the
plant development85
.
The potent physiological activity of many alkaloids has also led to
their use as pharmaceuticals, stimulants, narcotics and poisons. Alkaloids
currently in clinical use include the analgesics morphine and codeine, the
anticancer agent vinblastine, the gout suppressant colchicine, the muscle
relaxant (+) tubocurarine, the antiarrythemic ajmalicine, the antibiotic
sanguinarine and the sedative scopolamine. The plant alkaloids like caffeine
in tea and coffee and nicotine in all preparations (smoking, chewing) of
tobacco are widely consumed daily.83
1.2.5. Sugars and their derivatives
Sugars are the first complex organic compounds formed in the plant as
the result of photosynthesis and are the major sources of respiratory energy.
They also play a number of ecological roles, in plant- animal interaction, in
protection from wounding and infection and in the detoxification of foreign
substances. They can be classified as monosaccharides, oligosaccharides,
sugar alcohols and cyclitols86
. They are usually the food reservoirs in plant.
Glycerol is a building block of plant lipids, mannitol is common in higher
plants and the main function of sugar alcohols is as storage of energy and
osmo-regulation87
. The cyclitols function as intermediates in the synthesis of
different oligosachcharides88
.
The bulk of the carbohydrates occur in plants in the bound form,
attached to a range of different aglycones as the glycosides. Many studies
have shown that glycosylation reactions could be involved in the biosynthesis,
modification, transportation and storage of other secondary metabolites. It is
now recognized that the glycosylation of low-molecular-weight compounds of
plants, by adding a sugar moiety to the acceptors, usually changes acceptors
14
in terms of their bioactivity, stability, solubility, subcellular localization and
binding property to other molecules, and this possibly reduces the toxicity of
endogenous and exogenous toxic substances89
. Hence it is thought to be one
of the most important modification reactions towards plant secondary
metabolites, and plays a key role in maintaining cell homeostasis, thus likely
participating in the regulation of plant growth, development and in defense
responses to stress environments90,91
. For example during fungal attack, plants
form glycosidic bonds to detoxify the toxicity of pathogens92
. In the lignin
biosynthesis pathway, lignin monomers (coumaryl, coniferyl and sinapyl
alcohols) need to be translocated from the cytosol to the cell wall, where they
are polymerized into lignin. Here the glucosides of lignin monomers have
been considered as the transport forms93
. Glycosylation is usually the last step
of flavonol biosynthesis metabolism, probably indicating a requirement of
stabilization, reactivity or translocation. Multiple additions of sugar moieties
to a given compound, in parallel or in chains, give rise to a broad spectrum of
secondary metabolites, thus contributing to their unique properties. An
example is that one single flavonol, quercetin, has 300 different glycosides
naturally occurring in plants94
.
The plant secondary metabolites have large economical importance
because, these compounds are connected with the important traits of plant
itself, e.g., colour or fragrance of flowers, taste and colour of food, and
resistance against pests and diseases and also for the production of fine
chemicals such as drugs, antioxidants, flavors, fragrances, dyes, insecticides
and pheromones. For centuries, India, China, Egypt and Greece have led the
world in the use of natural products for healing. The folkloric medicine based
on judicious use of different plant parts has played a key role in reducing
human sufferings and counteracting diseases. In fact, modern pharmacology
arose from the traditional use of plant products as medicines, and even today
many therapeutic drugs are the plant secondary metabolites (e.g., morphine,
15
digoxin, atropine, ephedrine, atremisinin, vincristine,paclitaxel) or plant
secondary metabolite derivatives (e.g., codeine, buprenorphine, warfarin,
docetaxel)
According to an analysis conducted by Newman and coworkers, 42%
of all drugs approved from 1983 to 1994 originated from natural products and
more than 60% of all approved anti-infective and anti-cancer drugs in the
same period were derived from natural products95
. Natural products provide
greater structural diversity than standard combinatorial chemistry and the
chemical novelty associated with natural products is higher than that of any
other source. Indeed, 40% of the chemical scaffolds in a published database of
natural products are absent from synthetic chemistry96
. Industrially, secondary
metabolites serve as the sources of oils, both volatile and fixed, flavour and
fragrances, resins, gums, natural rubber, waxes, saponins and their
surfactants, dyes, pharmaceuticals, plants and insect growth regulators, and
many other specialty products.
Plant being a very complex organism producing millions of
compounds at a time, the isolation of the secondary metabolites becomes a
tedious task. Until recently, large-scale studies of plant metabolites have been
limited by the time-consuming and costly nature of available technology.
With the tremendous advance in the natural product chemistry and the
development of sophisticated techniques and improved chromatographic
separation methods, this difficulty is overcome. The newer spectroscopic
techniques such as two-dimensional high resolution NMR Spectroscopy, IR
and Raman Spectroscopy, Mass Spectroscopy and X-ray Crystallographic
Analysis have simplified the structural elucidation of new natural products.
16
REFERENCES
1. Dewick PM (2003) Medicinal natural products, a biosynthetic
approach II Edition, John Wiley and Sons, Ltd, England:7
2. Levitt J (1974) Introduction to plant physiology, The C V Mosby
Company, St. Louis:171-177
3. Collin HA (2001) Secondary product formation in plant tissue cultures.
Plant Growth Regulation 34:119–134,
4. Yazaki K, Sugiyama A, Morita M, Shitan N (2008) Secondary
transport as an efficient membrane transport mechanism for plant
secondary metabolites. Phytochem Rev 7:513-524
5. Yazaki K (2006) ABC transporters involved in the transport of plant
secondary metabolites. FEBS Letters 580:1183-1191
6. Verpoorte R, van der Heijden R, Memelink J (2000) Engineering the
plant cell factory for secondary metabolite production. Transgenic
Research 9:323–343
7. Yeoman MM, YeomanCL (1996) Tansley Review No. 90
Manipulating secondary metabolism in cultured plant cells. New
Phytol. 134:553-569
8. Kähkönen MP, Hopia AI, Heinonen M (2001) Berry phenolics and
their antioxidant activity. J Agric Food Chem 49:4076–4082.
9. Häkkinen SH, Törrönen AR (2000) Content of flavonols and selected
phenolic acids in strawberries and Vaccinium species: influence of
cultivar, cultivation site and technique. Food Res Int 33:517–524.
10. Sudha G, Ravishankar GA (2002) Involvement and interaction of
various signaling compounds on the plant metabolic events during
17
defense response, resistance to stress factors, formation of secondary
metabolites and their molecular aspects. Plant Cell, Tissue and Organ
Culture 71:181-212
11. Feeny PP (1968) Effect of oak leaf tannins on larval growth of the
winter moth Operophtera brumata. J Insect Physiol 14:805-817
12. Palo RT, Robbins CT (eds) (1991) Plant defences against mammalian
herbivory. CRC press, Boca Raton:133-166
13. Rhoades DF (1979) Evolution of plant chemical defense against
herbivores. In: Rosenthal GA, Janzen DH (eds) Herbivores: their
interaction with secondary plant metabolites. Academic Press, New
York:4-54
14. Halligan JP (1975) Toxic terpenes from Artemisia californica. Ecology
56:999-1003
15. Inderjit KMM (1996) Plant phenolics in allelopathy. Bot Rev 62:186-
202
16. Hartmann T (1996) Diversity and variability of plant secondary
metabolism: a mechanistic view. Entomologia Experimentalis
Applicata. 80:177-188.
17. Wink M (2003) Evolution of secondary metabolites from an ecological
and molecular phylogenetic perspective. Phytochemistry 64 (1):3-19.
18. Dewick PM (2003) Medicinal natural products, a biosynthetic
approach II Edition, John Wiley and Sons, Ltd, England:121
19. Bruneton J (1999) Pharmacognosy and Phytochemistry of Medicinal
Plants, 2nd edn. Lavoisier Publishing, Paris
18
20. Dixon RA, Sumner LW (2003) Legume Natural products:
Understanding and manipulating complex pathways for human and
animal health. Plant Physiol 131:878-885
21. Dixon RA, Ferreira D (2002) Genistein. Phytochem 60:205-211
22. Lamartiniere CA (2000) Protection against breast cancer with
genistein: a component of Soy. Am J Clin Nutr 71:1705S-1707S
23. Alekel DL, St Germain A, Pererson CT, Hanson KB, Stewart JW,
Toda T (2000) Isoflavon- rich soy protein isolate attenuates bone loss
in the lumbar spine of peri- menopausal women. Am J Clin Nutr
72:844- 852
24. Uesugi T, Toda T, Tsuji K, Ishida H (2001) Comparative study on
reduction of bone loss and lipid metabolism abnormality in
ovariectomized rats by soy isoflavones, daidzin, genistein and glyctin.
Biol Pharm Bull 24:368- 372
25. Dixon RA, Steele CL (1999) Flavonoids and isoflavonoids - a gold
mine for metabolic engineering. Trends Plant Sci 4:394-400.
26. Harborne JB, Williams CA (2000): Advances in flavonoid research
since 1992. Photochemistry 55: 481–504
27. Treutter D (2006) Significance of flavonoids in plant resistance: a
review. Environ. Chem. Lett. 4:147-157.
28. Shahidi F, Naczk M (2004) Phenolic compounds in fruits and
vegetables. In: Phenolics in food and nutraceutical, CRC Press, Boca
Raton:131–156
19
29. Ates O, Cayli S, Altinoz E, Gurses I, Yucel N, Sener M, Kocak A,
Yologlu S (2007) Neuroprotection by resveratrol against traumatic
brain injury in rats. Mol Cell Biochem 294:137-144
30. Delmas D, Jannin B, Latruffe N (2006) Resveratrol: preventing
properties against vascular alterations and ageing. Mol Nutr Food Res
49:377- 395
31. Vitrac X, Krissa S, Decendit A, Deffieux G, Merillon JM (2004)
Grapevine polyphenols and their biological effects. In: KG Ramawat
(ed) Biotechnology of Medicinal Plants, Science Publishers, Enfield,
CT:33
32. Archer AW (1988) Determination of safrole and myristicin in nutmeg
and mace by high performance liquid chromatography. J Chromatogr.
438:117- 121
33. Dietrich H, Rechner A, Patz CD (2004) Bioactive compounds in fruit
and juice. Fruit Process 1:50–55
34. Dyakov YT (2007) Comprehensive and molecular phytopathology,
Elsevier: 285-286
35. Fresco P, Borges F, Diniz C, Marques MPM (2006) New insights on
the anticancer properties of dietary polyphenols. Med Res Rev 26:747–
766
36. Marques MPM, Borges F, Sousa JB, Calheiros R, Garrido J, Gaspar A,
Antunes F, Diniz C, Fresco P (2006) Evaluation of anticancer and anti-
inflammatory properties of hydroxycinnamic derivatives. Lett Drug
Design Dev 3:316–320
20
37. Silva FA, Borges F, Guimarães C, Lima JL, Matos C, Reis S (2000)
Phenolic acids and derivatives: studies on the relationship among
structure, radical scavenging activity, and physicochemical parameters.
J Agric Food Chem 48:2122–2126
38. Siquet C, Paiva-Martins F, Lima JL, Reis S, Borges F (2006)
Antioxidant profile of dihydroxy-and trihydroxyphenolic acids-a
structure-activity relationship study. Free Radic Res 40:433–442
39. Que F, Mao L, Pan X (2006) Antioxidant activities of five Chinese rice
wines and the involvement of phenolic compounds. Food Res Int
39:581–587
40. Nichenametla SN, Taruscio TG, Barney DL, Exon JH (2006) A review
of the effects and mechanism of polyphenolics in cancer. Crit Rev
Food Sci Nut 46:161–183
41. Prats E, Galindo JC, Bazzalo ME, León A, Macías FA, Rubiales D,
Jorrín JV (2007) Antifungal activity of a new phenolic compound from
capitulum of a head rot-resistant sunflower genotype. JChem Ecol
33:2245–2253
42. Okunade A, Hufford C, Clark A, Lentz D (1997) Antimicrobial
properties of the constituents of Piper aduncum. Phytotherapy Res.
11:142–144
43. Tsuda H, Ishitani Y, Takemura Y, Suzuki Y, Kato T (1997) 6-acetyl-8-
hydroxy-2,2-dimethylchromene, an antioxidant in sunflower seeds; Its
isolation and synthesis and antioxidantactivity of its derivatives.
Heterocycles 44:139–142
44. Olsson ME, Gustavsson KE, Andersson S, Nilsson A, Duan RD (2004)
Inhibition of cancer cell proliferation in vitro by fruit and berry
21
extracts and correlations with antioxidant levels. J Agric Food Chem
52:7264–7271
45. Rayanil K, Bunchornmaspan P, Tuntiwachwuttikul P (2011) A New
Phenolic Compound with Anticancer Activity from the Wood of
Millettia leucantha. Arch Pharm Res 34(6):881-886
46. Bilusic TK, Schnäbele K, Schmöller I, Uzelac VD, Krisko A,
Dejanovic B, Milos M, Pifat G, (2009) Antioxidant activity versus
cytotoxic and nuclear factor kappa B regulatory activities on HT-29
cells by natural fruit juices. Eur Food Res Technol 228:417–424
47. Fuss E (2003) Lignans in plant cell and organ cultures: An overview.
Phytochemistry Reviews 2:307–320
48. South PK, Miller DD (1998) Iron binding by tannic acid: effects of
selected ligands. Food Chem 63:167–172
49. House WA (1999) Trace element bioavailability as exemplified by iron
and zinc. Field Crops Res 60:115–141
50. Wang RS, Kies C (1991) Niacin, thiamin, iron and protein status of
humans as affected by the consumption of tea (Camellia sinensis)
infusions. Plant Foods Hum Nutr 41:337–353
51. Tamir M, Alumot E (2006) Inhibition of digestive enzymes by
condensed tannins from green and ripe carobs. J Sci Food Agric
20:119–202
52. Oh HI, Hoff JE (2006) pH dependence of complex formation between
condensed tannins and proteins. J Food Sci 52:1267–1269
22
53. Manchado PS, Cheynier V, Moutounet M (1999) Interactions of grape
seed tannins with salivary proteins. Journal of Agricultural and Food
Chemistry 47(1): 42-47
54. Zwenger S, Basu C (2008) Plant terpenoids: applications and future
potentials. Biotechnology and Molecular Biology Reviews 3 (1):1-7
55. Oudin A, Courtois M, Rideau M, Clastre M (2007) The iridoid
pathway in Catharanthus roseus alkaloid biosynthesis. Phytochem Rev
6:259-276
56. Jansen BJM, de Groot A (2004) Occurrence, biological activity and
synthesis of drimane sesquiterpenoids. Nat Prod Rep 21:449-447
57. Lichtenthaler HK, Rohmer M, Schwender J (1997) Two independent
biochemical pathways for isopentenyl diphosphate and isoprenoid
biosynthesis in higher plants. Physiologia Plantarum 101:643-652.
58. Jux A, Gleixner W, Boland W (2001) Classification of terpenoids
according to the methylerythritolphosphate or the mevalonate pathway
with natural C-12/C-13 isotope ratios: dynamic allocation of resources
in induced plants. Angew Chem Int Ed Engl. 40: 2091–2093
59. Ali M, Techniques in Terpenoid Identification, Birla Publications,
Delhi:1
60. Miro M (1995) Cucurbitacins and their pharmacological effects.
Phytother Res 9:159-168
61. Brielmann HL, Setzer WN, Kaufman PB, Kirakosyan A, Cseke LJ
(2005) Phytochemicals: the chemical components of plants. In: Cseke
LJ, Kirakosyan A, Kaufman PB, Warber SL, Duke JA, Brielmann HL
(eds) Natural Products from Plants. Taylor Francis, Boca Raton, FL:1
23
62. Dewick PM (2003) Medicinal natural products, a biosynthetic
approach II Edition, John Wiley and Sons, Ltd, England:167
63. Giuliano1 G, Tavazza R, Diretto G, Beyer P, Taylor MA (2008)
Metabolic engineering of carotenoid biosynthesis in plants. Trends in
Biotechnology 26(3):139-145
64. Kappers IF, Aharoni A, Van Herpen T, Luckerhoff L, Dicke M,
Bouwmeester HJ (2005). Genetic engineering of terpenoids
metabolism attracts bodyguards to Arabidopsis. Science 309:2070-
2072.
65. Kessler A, Baldwin T (2001) Defensive function of herbivore-induced
plant volatile emission in nature. Science 291:2141-2144
66. Cheng A, Lou Y, Mao Y, Lu S, Wang L, Chen X (2007). Plant
terpenoids: Biosythesis and ecological functions. J Integrative Plant
Biol 49:179-186
67. Andrews RE, Parks LW, Spence KD (1980). Some effects of Douglas
fir terpenes on certain microorganisms. App. Environ. Microbiol.
40:301-304
68. Harborne JB (1973) Phytochemical Methods, Chapman and Hall Ltd,
London:56-59
69. Hertweck C (2009) The Biosynthetic logic of polyketide diversity.
Angew Chem Int Ed 48:4688-4716
70. Gershenzon J (1994) Metabolic costs of terpenoid accumulation in
higher plants. J Chem Ecol 20:1281–1328
24
71. Wittstock U, Gershenzon J (2002) Constitutive plant toxins and their
role in defense against herbivores and pathogens. Curr Opin Plant Biol
5:300–307
72. Guillet G, Lavigne ME, Philogene BJR, Arnason JT (1995) Behavioral
adaptations of two phytophagous insects feeding on two species of
Asteraceae. J Insect Behav 8:533
73. Harborne JB (1973) Phytochemical Methods, Chapman and Hall Ltd,
London :159
74. Kelly PJ, Bones AM, Rossiter JT (1998) Sub-cellular
immunolocalization of the glucosinolate sinigrin in seedlings of
Brassica juncea. Planta 206:370–377
75. Thangstad OP, Bones AM, Holton S, Moen L, Rossiter JT (2001)
Microautoradiographic localisation of a glucosinolate precursor to
specific cells in Brassica napus L. embryos indicates a separate
transport pathway into myrosin cells. Planta 213:207–213
76. Ramawat KG, Dass S, Mathur M, (2009) The chemical diversity of
bioactive molecules and therapeutic potential of medicinal plants In:
Ramawat KG (ed.) Herbal Drugs: Ethnomedicine to Modern Medicine,
Springer-Verlag, Berlin Heidelberg :16-21
77. Ketabchi S, Shahrtash M (2011) Effects of methyl jasmonate and
cytokinin on biochemical responses of maize seedlings infected by
fusarium moniliforme, Asian J Exp Biol Sci 2 (2):299-230
78. Mok DWS, Mok MC (2001). Cytokinin metabolism and action. Annu
Rev Plant Physiol Plant Mol Biol 52:89–118
25
79. Maiti M, Kumar GS (2007) Protoberberine alkaloids: Physicochemical
and nucleic acid binding properties. Top Heterocycl Chem 10:155–209
80. Kutchan T (1995) Alkaloid biosynthesis – the basis for metabolic
engineering of medicinal plants. Plant Cell 7:1059–1070
81. Kuramoto M, Arimoto H, Uemura D (2003) Studies in bioactive
marine alkaloids. J Synth Org Chem Jpn 61:1099-1105
82. Kuramoto M, Arimoto H, Uemura D (2004) Bioactive marine
alkaloids. A review. Mar Drugs 1:39-54
83. Ramawat KG (2007) Secondary metabolites in nature. In: Ramawat
KG, Merillon JM (eds) Biotechnology: Secondary Metabolites,
Science Publishers, Enfield, CT:21
84. Wink M (2000) Biochemistry of Plant Secondary Metabolism. Annual
Plant Review 2, Academic, Sheffield, UK:151
85. Nagasampagi BA, Bhat SV, Sivakumar M (2005) Chemistry of natural
products, Narosa Publishing House, NewDelhi:241
86. Harborne JB (1973) Phytochemical Methods, Chapman and Hall Ltd,
London :212-213
87. Lewis DH, Smith DC (1967a) Sugar alcohols in fungi and green plants
II. Method of detection and estimation. New Phytologist 66:185-204
88. Anderson L, Wolter KE (1966) Cyclitols in Plants: Biochemistry and
Physiology. Annual Review of Plant Physiology 17:209-222
89. Bowles D, Isayenkova J, Lim EK, Poppenberger B (2005).
Glycosyltransferases: managers of small molecules. Curr Opin Plant
Biol 8:254–263
26
90. Jones P, Vogt T (2001) Glycosyltransferases in secondary plant
metabolism: tranquilizers and stimulant controllers. Planta 213:164–
174
91. Lim EK, Bowles DJ (2004) A class of plant glycosyltransferases
involved in cellular homeostasis. EMBO J 23:2915–2922
92. Poppenberger B, Berthiller F, Lucyshyn D, Sieberer T, Schuhmacher
R, Krska R, Kuchler K, Gloss J, Luschnig C, Adam G (2003)
Detoxification of the fusarium mycotoxin deoxynivalenol by a UDP
glucosyltransferase from Arabidopsis thaliana. J Biol Chem
278:47905–47914
93. Lim EK, Jackson RG, Bowles DJ (2005b) Identification and
characterisation of Arabidopsis glycosyltransferases capable of
glucosylating coniferyl aldehyde and sinapyl aldehyde. FEBS Lett
579:2802–2806
94. Wang J, Hou B (2009) Glycosyltransferases: Key players involved in
the modification of plant secondary metabolites. Front Biol China
4(1):39–46
95. Cragg GM, Newman DJ, Snader KM (1997) Natural products in drug
discovery and development. J Nat Prod 60:52-60
96. Henkel T (1999) Statistical investigation into the structural
complimentarity of natural products and synthetic compounds. Angew
Chem, Int Ed Engl 38:643-647.