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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5666_Библиотеки_им_академика_М_И_Перельмана
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Introduction to Fundamental Natural Compounds
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sesquiterpenes (Dewick, 2002). At rst, it was thought that the cytosolic
MVA pathway is the only way to produce all sesquiterpenes. Recent studies,
however, revealed that provided or by both biosynthetic routes (Adam
and Zapp, 1998) or by the DXP pathway, certain sesquiterpenes derive
from isoprene units (Dudareva et al., 2005; Piel et al., 1998). Transport of
isoprenoid precursors to the cytosol from the plastids can well explain this
phenomenon (Bick and Lange, 2003).
A sesquiterpene phytohormone, abscisic acid promotes seed dormancy
and stomatal closure and is induced drought. Other sesquiterpenes join in
in tri-trophic herbivore-plant-parasite connections (Dudareva et al., 2006).
The sesquiterpenes (E)-α-bergamotene and the (E)-β-farnesene, in maize
infected with lepidopteran larvae, appeal to the parasitic wasp Cotesia
marginiventris (Schnee et al., 2006). Upon attack of larvae of the beetle
Diabrotica virgifera, maize roots release (E)-β-caryophyllene to appeal to
the parasitic nematode Heterorhabditis megidis (Rasmann et al., 2005).
A pentacyclic lactone group is present in many sesquiterpenes and
is hence named sesquiterpene lactones. In the family Asteraceae, these
compounds are abundant. Sesquiterpene lactones, because of their bitter
taste, apparently act as feeding deterrents of herbivores (Heinrich et al.,
1998). Anti-inammatory effects are often shown by the pharmacologically
active sesquiterpene lactones because of the inhibition of the transcription
factor NF-κB that mediates inammation and immunological responses (Lyb
et al., 1998). For example, sesquiterpenes with such activities are present in
one of the most popular medicinal plants, chamomile (Matricaria recutita).
Some sesquiterpene lactones have antimigraine action, e.g., parthenolide
from feverfew (Tanacetum parthenium), which is mediated by inhibition of
serotonin secretion and platelet aggregation (Dewick, 2002).
Figure 1.18: Linear and cyclic sesquiterpenes.
Source: https://www.mdpi.com/1422-0067/20/18/4562/htm.
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Natural Compounds: An Introduction
Structural requirement for the biological activities of sesquiterpene lactones
is alkylated proteins and α, β-unsaturated lactone that serve as nucleophiles
mainly at their thiol groups. Contrary to this, cytotoxicity, and allergenicity
of sesquiterpene lactones with α, β-unsaturated lactone is caused by the
alkylation of proteins.
Against malaria, artemisinin is a new encouraging agent. It is a tetracyclic
sesquiterpene, structurally with an unusual 1,2,4-trioxane ring and a sixmembered lactone ring. It is present in Artemisia annua (qinghao), which
has been used to treat fevers, including malaria for centuries in Traditional
Chinese Medicine. A request of the president of North Vietnam, Ho Chi
Minh, to the Chinese government for a cure against malaria was the starting
point of the discovery of artemisinin during which the president of Ho Chi
Minh wanted to port his troops in the malaria-infested jungles during the
American/Vietnamese war (Hsu, 2006). The antimalarial activity of an
ether extract from A. annua was revealed during a screening of plants used
in Traditional Chinese medicine in 1971 and artemisinin (qinghaosu) was
isolated as the active principle in the late 1970s. The mechanism of action of
artemisinin is still being examined. Other mechanisms, e.g., the production
of reactive oxygen species or alkylation of biological macromolecules
are discussed, but most probably, it interferes with a sarco-endoplasmic
reticulum calcium ATPase (SERCA) of Plasmodium falciparum (White,
2008). A necessary structural feature, the peroxide bridge, is required for
antimalarial activity. Quinine, on the other hand, destroys already young
erythrocytic forms of the parasite Plasmodium, hence curing malaria at an
early stage. Two semisynthetic analogs, artesunate, and artemether, with
higher efcacy in comparison to artemisinin, were established and now used
as rst-line therapy against malaria in blend with other antimalarial drugs
like the lumefantrine and quinine analogs. Since A. annua contains only
0.01–1.5% of artemisinin, a huge demand for artemisinin cannot be covered
at low cost by isolation of the sesquiterpene from the plant after the success
of artemisinin (Covello et al., 2007). Methods to deliver the inuential drug
at a reasonable price for the people in malaria-endemic areas are raising
biotechnological production of the artemisinin precursor artemisinic acid
by cloning the biosynthetic genes from A. annua or breeding of A. annua
plants with raised artemisinin levels (Covello et al., 2007) and engineering
the pathway into the bacterium Escherichia coli or yeast (Chang et al., 2007;
Ro et al., 2006).
Introduction to Fundamental Natural Compounds
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1.4.3. Diterpenes
Diterpenes are synthesized from three molecules of IPP and DMAPP
originated from the plastic DXP pathway yielding the C
geranylgeranyl diphosphate (GGPP). GGPP is the precursor of the lipophilic
phytyl side chain of plastoquinone and chlorophyll. GGPP can also undergo
rearrangements and cyclization, like the smaller terpenes, to various different
structures. Gibberellins are tetracyclic diterpenes that promote shoot
elongation, seed germination and flowering by serving as phytohormones
and (Bishopp et al., 2006). Diterpenes are constituents of conifer oleoresin
like levopimaric and abietic acid and function as a defense against pathogens
and herbivores. After elimination of mono- and sesquiterpenes (turpentine)
by distillation from oleoresin, the solid diterpene fraction is termed
colophonium and utilized on the bows of string instruments. The mono- and
sesquiterpene comprising distillate is utilized as oil of turpentine for the
thinning of varnishes and paints (Figure 1.19).
metabolite
20
Figure 1.19: Structures of diterpenes.
Source: https://www.researchgate.net/gure/The-structures-of-diterpenoids-1-6_g2_232319698.
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Derived from two molecules phenylalanine, the powerful cytostatic compound
paclitaxel (Taxol®) is a diterpene with an N-benzoyl phenylisoserinoyl side
chain. In 1966, Paclitaxel, by bioactivity-directed fractionation, was first
isolated from the bark of the Pacific yew (Taxus brevifolia), and 5 years
later, its structure was elucidated (Wani et al., 1971). A unique mechanism
is responsible for its anticancer activity. Paclitaxel attaches to microtubules,
steadies them against depolymerization, and hence blocks cell proliferation
(Schiff and Horwitz, 1980). For the therapy of ovarian, breast, and lung
cancers, cancers of neck and head, and Kaposi’s sarcoma. Paclitaxel occurs
in the bark of T. brevifolia, only in relatively low amounts (0.01–0.02%),
and the trees breed slowly, so there was a requirement of other sources to
provide an adequate supply of the diterpene for industrial production. Today,
paclitaxel is produced either by semisynthesis from 10-deacetylbaccatin
III and baccatin III or from tissue cultures of various Taxus, which can be
extracted in adequate quantities from twigs or leaves of the common yew (T.
baccata), a tree that breeds much faster than T. brevifolia.
Natural Compounds: An Introduction
1.4.4. Triterpenes and Steroids
Triterpenes are produced by the MVA pathway from two molecules of FPP,
which are linked by tail-to-tail condensation to squalene. Several structures,
mainly tetra- or pentacyclic. 2,3-Oxidosqualene is produced by the
cyclization of its metabolite 2,3-oxidosqualene followed by methyl shifts
and rearrangements which is also the precursor of plant steroids. In this way,
it is then converted to the C27 compound cholesterol after it is closed to the
triterpene cycloartenol, h the loss of three methyl groups. In both steroids
and triterpenes, the oxygen of 2,3-oxidosqualene is typically reserved as the
hydroxyl group at C-3.
Many plants, in contrast to animals, where cholesterol is the major sterol,
plant sterols are ethylated or methylated at C-24 of the side chain, e.g.,
stigmasterol, and campesterol. In plants, these phytosterols are ingredients
of biomembranes and affect their permeability. In animals, phytosterols
constrain the absorption of cholesterol. They are more readily incorporated
into the micelles since they are more lipophilic than cholesterol. Therefore,
as cholesterol-lowering food additives, esters of phytosterols are used
(Dewick, 2002). Derivatives of campesterol, brassinosteroids are a group
of plant hormones. They control numerous biological processes, e.g., seed
germination, stem elongation, and leaf expansion (Figure 1.20) (Bishopp et
al., 2006).
Introduction to Fundamental Natural Compounds
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Figure 1.20: Sterols derived from 2,3-oxidosqualene.
Source: https://link.springer.com/chapter/10.1007/978-0-387-85498-4_1.
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1.4.5. Saponins
Triterpene saponins are extensively dispersed among eudicot plants, for
instance, in Caryophyllaceae, Araliaceae, Primulaceae, and Fabaceae
families. Monocots, instead, preferably collect steroidal saponins, which
are plentiful in the Dioscoreaceae, Agavaceae, and Yuccaceae. Triterpenoid
saponins often comprise of b-amyrin (oleanane) or the tetracyclic dammarane
backbone as aglycone or lupine skeleton or pentacyclic α-amyrin (ursane).
This aglycone is connected with one to three carbohydrate chains comprising
uronic acids or up to six sugar molecules (Hostettmann and Marston, 1995).
The first sugar chain is linked to the hydroxy group at C-3 of the triterpene
backbone. If two or more carbohydrate chains are existing, they are typically
associated with carboxy groups or hydroxy at C-30 or C-28. Steroid saponins
can be categorized into two groups, furostanols, and spirostanols. The side
chain of cholesterol is utilized to form a tetrahydrofuran ring in furostanols,
and the hydroxy group at C-26 is glycosylated. A second oxygen-containing
heterocycle is formed upon cleavage of this sugar moiety, hence producing a
spirostanol. The structure of steroidal glycoalkaloids and spirostanol saponins
are the same, excluding that the oxygen in the six-membered heterocycle of
the spiro function is exchanged by nitrogen. Steroidal saponins carry a sugar
chain at the C-3 hydroxy group as in the case of the triterpene saponins
(Figure 1.21).
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Natural Compounds: An Introduction
Figure 1.21: Triterpene and steroid saponins.
Source: https://www.researchgate.net/gure/Triterpene-and-steroid-saponins_
g23_226934227.
The Latin word “Sapo” is the origin of the name saponin also known
as soap. This denotes the properties of saponins, which consist of soaps of
a hydrophilic moiety (sugars) and a lipophilic moiety, and when shaken in
an aqueous solution, it produced foam. Plants like soapbark tree (Quillaia
Saponaria) and soapwort (Saponaria ofcinalis) were hence used as
Introduction to Fundamental Natural Compounds
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35
detergents. Today, in detergents, cosmetics, and as foaming agents in
soft drinks, isolated saponins or extracts of saponin-containing plants are
used (Güçlü-Üstündag and Mazza, 2007). In a process called hemolysis,
saponins destroy red blood cells, because they complex sterols of the plasma
membrane and hence raise the membrane permeability. The antifungal and
antimicrobial activities of saponins as well as their function as detergents is
due to their ability to initiate a membrane-permeabilizing effect. Stronger
antifungal and hemolytic effects, in general, are shown by only one
sugar chain (monodesmosides) than saponins with two oligosaccharide
chains (bisdesmosides). In the case of wounding by a specic hydrolase,
bisdesmosidic saponins can be assumed of as prodrugs that are cleaved like
glucosinolates and glucosides, converted into active defense compounds
(Osbourn, 1996). However, for the biological activity of saponins, one
sugar chain is necessary, whereas other natural products when glycosylated
usually lose their activity.
Saponins are nontoxic when taken orally because they are absorbed
poorly, and the sugar chain is hydrolyzed, which is signicant for their
hemolytic properties. Contrary to this, saponins damage the membranes of
the gills and are hence toxic to sh (Hostettmann and Marston, 1995). To
stupefy and poison sh, plant materials rich in saponins have therefore been
used. Conversely, the sh under sapanin inuence are not toxic to humans,
and such sh can then be caught without difculty.
There are some known sweet saponins as well although most saponins
have a bitter taste. Glycyrrhizic acid from a β-amyrine type triterpene,
licorice root (Glycyrrhiza glabra) connected to two molecules of glucuronic
acid, is 50 times sweeter than sucrose (table sugar). To prepare sweeteners
and candies (licorice), licorice extracts are used. They are also used as an
anti-inammatory agent and as a mild expectorant. Inhibition of an enzyme
causes an anti-inammatory effect that inactivates cortisol. Contrary to this,
this may also cause side effects such as excretion of potassium, e sodium
and water retention.
In conventional medicine in China, Japan, and Korea, the roots of
ginseng (Panax ginseng) have been used for several 1000 years. To help the
body to cope with stress, during convalescence and to improve performance,
it is used as an adaptogen (Radad et al., 2006). Active constituents are
saponins, mostly of the dammarane form, comprising two or three sugar
side chains. The ginseng aglycones protopanaxatriol and protopanaxadiol
display promising anticancer activities, and a preparation comprising
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Natural Compounds: An Introduction
ginseng aglycones for the therapy of various tumors as a single agent or
in combination with paclitaxel has been given provisional authorization in
China.
The triterpene sapogenins ursolic acid, ursolic acid, and betulinic acid
show anti-inammatory and cytotoxic effects, and based on their structure’s
new anticancer agents and chemopreventive are being established (Liby et
al., 2007). Bevirimat derived from the betulinic acid is the rst member
of a novel class of maturase inhibitors, HIV therapeutics. The processing
of the HIV Gag protein is inhibited by these compounds and leads to noninfectious and defective particles (Li et al., 2003).
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