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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5944_Библиотеки_им_академика_М_И_Перельмана
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Introduction to Fundamental Natural Compounds
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19
the Silurian period about 400 million years ago with the advent of the rst
vascular plants. Lignin is the second most plentiful biopolymer on earth after
cellulose. Lignin is vital for the quality of wood, from an economic point
of view, but it is an unwanted constituent for the paper industry because its
oxidation causes the yellowing of paper. Lignin decreases the absorption
of nutrients and the digestibility of forage because it cannot be digested by
ruminants (Boerjan et al., 2003; Rouhi et al., 2000). Additionally, before
the production of biofuels, lignin has to be detached from lignocellulosecontaining plant material because it hampers the extraction and degradation
of cellulose. The use of lignin-degrading enzymes from bacteria or fungi and
the generation of genetically altered crops with altered lignin composition
and content are the possible strategies to make biofuel production better
(Weng et al., 2008).
Stereoselectively linking of two gnols at the central atoms of their side
chains forms lignans. The dimers are named neolignans if the monolignols
are formed by other types of coupling (Dewick, 2002). In the dimer, the last
carbon of one side chain of monolignol is missing in norligans. In more than
70 plant families, lignans were found, and because of their antibacterial,
antiviral, and antifungal properties, they serve as guards against pathogens
and herbivores (Saleem et al., 2005). Moreover, they are present in numerous
plant foods such as whole cereals, oilseeds, fruits, and vegetables. Specic
rich sources of lignans with more than 0.3 g/100 g are axseed, sesame, and
sesame seed with secoisolariciresinol (Figure 1.12) as major components
(Adlercreutz, 2007; Milder et al., 2005). These and several other lignans
can be transformed to the mammalian lignans enterolactone and enterodiol
by the intestinal microora (Figure 1.12). The two enterolignans are weak
phytoestrogens; they dilate steroid hormone concentrations by competing
for their metabolizing enzymes and crease the concentrations of sex
hormone-binding globulin in the plasma (Adlercreutz, 2007). It is presumed
that ingesting a diet rich induces the risk for breast and colon cancer and
advantages health. It is problematic, however, to point the advantageous
effects exclusively to lignans, since lignan-rich food typically comprises of
other health-promoting ingredients like bers or other polyphenols.
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Natural Compounds: An Introduction
Figure 1.12: Lignans of various origin.
Source: researchgate.net/gure/Lignans-of-various-origin_g12_226934227.
From Podophyllum peltatum or P. hexandrum (Berberidaceae), a
strong cytotoxic lignan is a podophyllotoxin (Figure 1.12). The mechanism
of action of podophyllotoxin is the same as the terpene indole alkaloids
VCR and vinblastine; by binding to tubulin, it inhibits cell division and
preventing its polymerization. This lignin is also used for the treatment of
warts but is too toxic for systematic application. It has derivatives that have
reduced toxicity such as etopophos, etoposide, and teniposide. They have an
inverted stereochemistry at C-4 and are prepared semi-synthetically from
4’-demethylpodophyllotoxin.
A new anticancer mechanism results from these changes, the
topoisomerase-DNA complexes stabilization which is analogous to that of
camptothecin. However, unlike camptothecin, the podophyllotoxin analogs
attack topoisomerase II, instead of topoisomerase I. To treat testicular cancer,
small cell lung cancer, and certain lymphomas, etoposide, and its prodrug
teniposide in combination with others are used. As therapy for childhood
acute lymphocytic leukemia, teniposide is used.
Introduction to Fundamental Natural Compounds
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1.3.2. Phenylpropenes and Benzenoids
Phenylpropenes originate from cinnamic acid with the common first step
of lignan and lignin biosynthesis. Compounds with a C
benzenoids result from the two carbons shortening of the cinnamic acid
side chain. 2-phenyl ethanol and phenylacetaldehyde are the other volatile
phenylpropanoid-related compounds. The shortening of phenylalanine by
carbon gives rise to these compounds (Pichersky and Dudareva, 2007).
Benzenoid and phenylpropene are lipophilic compounds with a distinctive
scent. After terpenoids, they comprise the second largest class of plant
volatiles. Terpenoid and benzenoid/phenylpropanoid volatiles in many
plants occur as a mixture, although typically one group gathers chiefly.
Various other volatiles originating from plants are derived from fatty acids
and amino acids in addition to these two major classes of natural products.
For the attraction of pollinators, as defense compounds or as seed dispersers,
each plant uses its cocktail of volatiles. Intoxication of herbivores, direct
deterrence or communicating the danger to other plants in the neighborhood,
or indirect attracting insect predators in case of tritrophic interactions are
mechanisms of the defense functions (Dudareva et al., 2006). Moreover,
many volatiles have antifungal and antibacterial properties (Kalemba and
Kunicka, 2003).
skeleton called
6-C1
Important oils with phenylpropenes are present, e.g., in the Myrtaceae,
Lauraceae, and Apiaceae families. Since antiquity, many of these
phenylpropene-containing plants have been used by humans as herbal
remedies and condiments. Cloves, native to the Maluku islands, are used
as a spice which are the unopened ower buds of the evergreen clove tree
(Syzygium aromaticum, Myrtaceae), but also as antiseptic and anesthetic
in dentistry. The phenylpropene eugenol is the major component and
active ingredient of essential oil from cloves (Figure 1.13). Cinnamomum
ceylanicum (Lauraceae), another evergreen tree from the tropics from Sri
Lanka, is the foundation of cinnamon bark with Tran’s cinnamaldehyde as the
chief avor constituent. In the antique world, cinnamon was highly-priced.
Some phenylpropenes are possibly carcinogenic, e.g., methyl eugenol,
safrole, and estragole. They need bioactivation which includes sulfation and
hydroxylation at the side chain to become toxic (Zhou et al., 2007).
The distinctive fragrance of many owers is attributed to the benzenoids.
For example, methyl benzoate is the main fragrance essential of Petunia
owers. Other benzenoids such as benzyl alcohol, benzaldehyde, methyl
salicylate, and benzyl acetate often contribute to the oral scents (Figure
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Natural Compounds: An Introduction
1.13) (Knudsen et al., 1993). The latter compound is responsible for the
analgesic effect and the distinctive smell of wintergreen (Gaultheria
procumbens, Ericaceae) (Dewick, 2002).
Figure 1.13: Phenylpropanoid and benzenoid volatiles.
Source: https://link.springer.com/chapter/10.1007/978-0-387-85498-4_1.
1.3.3. Polyketides
Polyketides are produced from two-carbon units originated from activated
acetate in the form of malonyl-CoA and acetyl-CoA. Polyketides preserve all
or most of their oxygen functions, unlike fatty acids, which also initiate from
these precursors. Highly reactive poly-β-keto intermediates are produced
in the course of polyketide biosynthesis, which regularly experiences
cyclization to 2-pyrone rings or six-membered aromatic.
Like the phenylpropanoids, many polyketides are phenolics, but the two
classes can be differentiated by the exchange pattern of the aromatic ring.
Phenolics originated from the phenylpropanoid pathway display an ortho
oxygenation pattern, while polyketides typically comprise oxygen functions
on alternate carbons (meta-position). Many polyketides may carry acyl
substituents on the sugar unit and are glycosylated.
Polyketides present in plants are not always completely produced from
acetate units, but frequently are of the mixed biosynthetic source. Terpenoid
building blocks or phenylpropanoid or sometimes both can be linked with
the acetate-derived backbone.
Moreover, amino acids or fatty acids can be sources of part of the carbon
skeleton derivation. A plethora of structurally varied compounds results
from this mixed assembly principle. Polyketide alkaloids attained when
nitrogen-containing or nitrogen precursors are combined into the polyketide
backbone will also be discussed.
Introduction to Fundamental Natural Compounds
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1.3.4. Polyketide Alkaloids
The piperidine alkaloids of poison hemlock (Conium maculatum) are
probably the most famous compounds of this class-to one used to execute the
Greek philosopher Socrates. The carbon skeleton of the piperidine alkaloids
in C. maculatum is usually synthesized from four acetate units while
piperidine alkaloids originate from the amino acid L-lysine (Leete, 1963,
1964). Only the nitrogen is the derivative of the L-alanine by transamination
(Roberts, 1971). The highest hemlock alkaloids levels are found in unripe
fruits (1.6%). However, it is accumulated in all plant parts (Dewick, 2002).
The two main hemlock alkaloids are coniine and γ-coniceine (Figure 1.14).
Piperidine alkaloids like coniine is present not only in C. maculatum, but
also in numerous Aloe species (Reynolds, 2005). These compounds cause
muscular tremor, paralysis, and death by respiratory paralysis and are
neurotoxic.
Figure 1.14: Different types of polyketide alkaloids.
Source: https://www.researchgate.net/gure/Different-types-of-polyketide-alkaloids_g18_226934227.
The carbon skeleton of naphthyl isoquinoline alkaloids is composed of
the same building blocks malonyl-CoA and C
CoA, although it is much more complex than that of the coniine alkaloids.
Every part of the naphthyl isoquinoline skeleton, isoquinoline moiety,
and naphthalene are derivatives of the six acetate units. Nitrogen which is
most likely derived from amino acid metabolism is incorporated only in
the isoquinoline part (Bringmann and Feineis, 2001). Naphthylisoquinoline
alkaloids are present only in the plant families Dioncophyllaceae and
Ancistrocladaceae that contain lianas from Africa and Southeast Asia.
Towards insects, they were revealed to have antifeedant properties and
units derived from acetyl-
2
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Natural Compounds: An Introduction
fungicidal activities, which might link to their physiological purpose.
During a screening by the U.S. National Cancer Institute, a dimeric naphthyl
isoquinoline, Michellamine B, from the liana Ancistrocladus korupensis
was discovered. It exhibited auspicious anti-HIV activity backing the fusion
of virus particles with the human cell membrane and hindering the viral
reverse transcriptase (McMahon et al., 1995). Other alkaloids of this class,
e.g., ancistrocladinium A and B and dioncophylline C (Figure 1.14) have
antileishmanial and antiplasmodial properties, respectively (François et al.,
1997; Ponte-Sucre et al., 2007).
The nitrogen in the backbone of acridone alkaloids, in contrast to the
earlier two classes of alkaloids, is not attained by transamination from an
amino acid. Instead, the part of the carbon skeleton and nitrogen of acridones
originate from N-methylanthraniloyl-CoA, which is a derivative of the
shikimate pathway. Moreover, three C
units are incorporated, which are
2
derived from malonyl CoA. By prenylation with dimethylallyl diphosphate
(DMAPP), the basic acridone skeleton can be altered, which can be tailed
by the creation of an additional heterocyclic ve-or six-membered ring. In
plants in the Rutaceae family, acridone alkaloids are present abundantly.
Acridones can intercalate DNA, due to their planar aromatic structure.
Promising anticancer activity has been shown by Acronycine (Figure 1.14)
from Acronychia baueri, but in clinical studies, it did not produce convincing
results. Benzoacronycine, a new derivative S23609-2 is a potent DNAalkylating agent and presently experiences phase I clinical trials (Léonce et
al., 2006).
1.4. TERPENOIDS
The largest class of natural products in plants, terpenoids, and also termed
isoprenoids comprise more than 40,000 diverse structures. They are derived
according to the number of isoprene molecules incorporated, and from
five-carbon isoprene units, they can be grouped into sesquiterpenes (C
hemiterpenes (C
such as rubber, diterpenes (C
Two different biosynthetic routes in plants are the origin of the terpenoids:
the plastid-located desoxyxylulose phosphate (DXP) pathway (also called
methylerythritol phosphate or MEP pathway) and the cytosolic mevalonic
acid (MVA) pathway. Both biosynthetic ways produce the activated isoprene
units-isopentenyl diphosphate (IPP), and DMAPP, which are connected by
tail-to-tail or head-to-tail linkage and consequently can experience cyclization
), triterpenes (C30), monoterpenes (C10), polyterpenes
5
), and tetraterpenes (C40) (Dewick, 2002).
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),
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and other alterations, e.g., rearrangements or oxidation. Steroids, triterpenes,
and triterpenoids are derived from MVA while diterpenes, hemiterpenes,
tetraterpenes, and monoterpenes originate from the DXP pathway (Figure
1.15). Although DXP and MVA are situated in different compartments,
there is an exchange between two biosynthetic ways, particularly from the
plastidial to the cytosolic pathway (Laule et al., 2003; Schuhr et al., 2003).
This has become chiefly obvious in the case of numerous sesquiterpenes,
which are manufactured from IPP and DMAPP units given by the DXP
pathway, but not from MVA (Dudareva et al., 2005; Piel et al., 1998).
Figure 1.15: Schematic overview of terpene biosynthesis in plants [DMAPP:
dimethylallyl diphosphate; DXP: desoxyxylulose phosphate; FPP: farnesyl
diphosphate; GGPP: geranylgeranyl diphosphate; GPP: geranyl diphosphate;
IPP: isopentenyl diphosphate; MVA: mevalonate].
Source: https://www.researchgate.net/gure/Fig-1-Schematic-overview-of-terpenoid-biosynthesis-in-plants-In-the-plastid_g1_49642213.
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Natural Compounds: An Introduction
1.4.1. Hemiterpenes
A volatile compound produced from DMAPP; isoprene is the most abundant
true hemiterpene from plants (Figure 1.16). In the plant kingdom, the
emission and production of isoprene are disseminated very extensively, and
species that produce this compound are present among ferns, angiosperms,
mosses, and gymnosperms. Many isoprene-emitting species are trees,
mainly poplar and aspen trees, and plants from the humid tropics. Isoprene
is released into the atmosphere and guards the leaves to endure short periods
of high temperature. Moreover, the tolerance of plants towards reactive
oxygen and ozone species is also increased (Sharkey et al., 2008).
Figure 1.16: Hemiterpene structures.
Source: https://slideplayer.com/slide/6537819/.
Another function of the hemiterpenes is by serving as signaling molecules.
The highly volatile hemiterpene methacrolein is emitted by the leaves of
sagebrush (Artemisia tridentata) (Figure 1.16), in addition to their volatile
compounds such as methyl jasmonate, monoterpenes, and hexenal when the
plant is impaired. This is observed by plants in their close neighborhood
and allows them to respond faster to a possible attack. A plant that is ready
in this way, is less probable to be injured by herbivores (Baldwin et al.,
2006). Besides, the natural products of mixed biosynthetic contain C
units
5
originated from DMAPP, e.g., prenylated avonoids, hyperforin, and hop
bitter acids.
1.4.2. Monoterpenes
One molecule IPP and one molecule DMAPP are generated from
monoterpenes that are in majority, linked by head-to-tail, resulting in alltrans geranyl diphosphate (GPP) (Figure 1.17). GPP can be folded into tri, bi-, and monocyclic structures and can experience alteration to produce
more than 1000 various monoterpenes. These lipophilic volatile compounds
are present in defensive resins of essential oils, floral scents, and conifers
and add to the distinctive aroma or flavor of many plants.
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27
Large amounts of monoterpenes can be gathered in specialized structures
because of their volatility. Several plant families such as Asteraceae and
Lamiaceae contain glandular trichomes with secretory cells that synthesize
terpenes and discharge them into a common subcuticular storage cavity
(Croteau et al., 2005). In the same way, a complex mixture of mono-, sesqui-,
and diterpenes, named oleoresin is accumulated by conifers in resin ducts
or blisters, which are enclosed by a layer of epithelial cells that produce
and discharge the terpenes into the lumen (Trapp and Croteau, 2001).
Similar to the conifers, several other plants gather monoterpenes in mixtures
comprising of the larger sesqui- and diterpenes, instead of monoterpenes
alone.
Monoterpenes have primary physiological functions of attraction
of pollinators, defense, and plant-plant communication (Mahmoud and
Croteau, 2002). In the example of the bark beetle and conifers, the role of
terpenes in plant-insect-relations has been mainly well-studied. Oleoresin
is secreted from the ducts, upon tissue damage by the beetle, or produced
newly. The volatile turpentine fraction of oleoresin is killing the beetles and
linked pathogenic fungi, which consists of biologically active mono- and
sesquiterpenes, e.g., pinene, and limonene. The residual non-volatile rosin
fraction containing diterpene resin acids solidies, after the evaporation
of turpentine, hence duping the predators and sealing the wound (Philipps
and Croteau, 1999). Monoterpenes in oleoresin act as olfactory signals,
despite the toxicity, that help the bark beetles to search their host. Ingested
monoterpenes are transformed into pheromones by the beetles that either
serve as anti-aggregation signals or attract more beetles. Moreover, conifer
monoterpenes involve in tritrophic interactions and appeal to insect predators
that nourish on bark beetles (Trapp and Croteau, 2001).
Figure 1.17: Mono- and bicyclic monoterpenes derived from geranyl diphosphate (GPP).
Source: https://www.researchgate.net/gure/Mono-and-bicyclic-monoterpenes-derived-from-geranyldiphosphate-GPP_g19_226934227.
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Natural Compounds: An Introduction
There are several applications of various monoterpenes in aromatherapy,
insecticides, perfumery, and cosmetics. Menthol is the most extensively used
monoterpene which is a constituent of essential oils from Mentha species.
It is present in oral health care products, tobacco products, pharmaceuticals,
and chewing gums (Croteau et al., 2005). Every year, more than 7,000 tons
of menthol are synthesized either from the steam-distilled essential oil of
corn mint (Mentha arvensis var. piperaceous) or by total synthesis. The
cooling sensation stirred by menthol is produced by the excitation of cation
channels that act as thermal receptors (Jordt et al., 2003).
(R) Limonene and perrillyl alcohol are the two monoterpenes with
auspicious anticancer effects (Mo and Elson, 2004). These two chemicals
persuade apoptosis and reduce translation of 3-hydroxy-3-methylglutarylCoA (HMG-CoA) reductase, an enzyme of the MVA pathway. For antitumor compounds, this compound is a likely target, because several
proteins are prenylated involved in cell growth and tumor cells have
raised HMG-CoA reductase levels. Since animals lack the alternative DXP
pathway, suppression of HMG-CoA reductase is adequate to reduce terpene
biosynthesis in humans.
Iridoids are monoterpenes having a six-membered oxygen heterocycle
hardened to a cyclopentane ring. The hydroxy group of the oxygen
is glucosylated, containing a heterocycle (dihydropyridine), hence,
transforming the enol-hemiacetal into an acetal (Figure 1.18). The
secoiridoids are produced by the cleavage of the cyclopentane ring of the
iridoid skeleton, which are biosynthetic building units of the MIAs and
the Ipecac alkaloids. Ants of the genus Iridomyrmex that synthesize these
metabolites as defense compounds are the origin of the name iridoids.
Iridoids are chemotaxonomic markers of the genera Galium (Rubiaceae),
Plantago (Plantaginaceae) genera Plantago (Plantaginaceae) in plants
and also happens repeatedly in Verbenaceae, Oleaceae, and Gentianaceae
(Dinda et al., 2007a, b). Many iridoids act as feeding deterrents because
they have an intense bitter taste (Seigler, 1998). Contrary to this, plants,
e.g., gentian (Gentiana lutea) with bitter-tasting iridoids and with its bitter
principle amarogentine and gentiopicroside, are utilized for the preparation
of tonics against dyspepsia and anorexia.
Condensation of DMAPP with two molecules of IPP produces
sesquiterpenes which comprise three isoprene units. Folding of the central
C
intermediate farnesyl diphosphate (FPP) can be performed into tri-, bi-,
15
or monocyclic systems. Usually, monoterpenes are more volatile than the
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