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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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Erythroxylaceae, and two species of the Moraceae (Biastoff and Dräger,
2007). Their high hydrophilicity is one important reason for their late
discovery, due to which they cannot be extracted with organic solvents
like alkaloids. Calystegines are sugar-copying glycosidase inhibitors. They
compete with polysaccharides, due to their structural similarity to sugars,
for binding at the active site of the glycosidase. The prevention of postprandial glucose peaks in patients with type II diabetes is, therefore, one
likely medicinal application for this group of metabolites. Moreover, for the
therapy of Morbus Gaucher calystegines might become beneficial, which is
a lysosomal storage disease that is caused by a mutation in the gene encoding
glucocerebrosidase.
Figure 1.5: Structures of calystegines A3, B1, and B2.
Source: https://www.researchgate.net/gure/Structures-of-calystegines-A-3-B1-and-B-2_g5_226934227.
On the mutated enzyme, calystegines were testied to act as chaperones
hence preventing its degradation and misfolding. However, it is still not
clear whether this hydrophilic polyhydroxylated alkaloid can be immersed
in the intestines and conveyed to the lysosomes of target cells (Biastoff and
Dräger, 2007).
1.2.6. Pyrrolizidine Alkaloids
A hydroxymethyl pyrrolizidine (necine base) compose the backbone of the
pyrrolizidine alkaloids that are usually esterified with branched aliphatic
di- or monocarboxylic acid (nucleic acids). The biosynthesis of the necine
base takes place from putrescine and spermidine, which in turn has origin
from arginine (Hartmann et al., 1988). Only for pyrrolizidine alkaloids of
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Natural Compounds: An Introduction
the lycopsamine and senecionine type, the origin of the nucleic acids have
been investigated; they are derivatives of amino acid metabolism (Stirling et
al., 1997; Weber et al., 1998). Figure 1.6 shows the major structural forms of
pyrrolizidine alkaloids. These alkaloids are normally stored and conveyed
as polar N-oxides in plants. Pyrrolizidines are present normally in the plant
families Fabaceae, Asteraceae, Orchidaceae, and Boraginaceae, although
random presence in some other families of plants have also been described
(Hartmann and Ober, 2000).
Figure 1.6: The ve major structural types of pyrrolizidine alkaloids. In plants,
these alkaloids occur mostly in the form of their N-oxides.
Source: https://link.springer.com/chapter/10.1007/978-0-387-85498-4_1.
Several pyrrolizidine alkaloids are mutagenic, hepatotoxic, and
carcinogenic. They are causes of veno-occlusive disease of the liver that
may result in cirrhosis and then liver failure. The ingestion of herbal
medicines containing these alkaloids and contamination of cereals with
pyrrolizidine-containing plants are the major reason for the intoxications
with the pyrrolizidines.
The presence of hydroxyl groups at C-7 and C-9, the double bond in
the necine base between C-1 and C-2, and esterication of at least one
Introduction to Fundamental Natural Compounds
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of these hydroxy groups with a branched carbon chain are the structural
features responsible for the genotoxicity (Frei et al., 1992). Esterication
can take place at C-7 and/or C-9 positions (Xia et al., 2008). In most insect
herbivores and vertebrates, the alkaloid N-oxides (PANO) are reduced to
their free bases in the gut. Cytochrome P450-dependent monooxygenases of
the liver then take up the reduced alkaloids and bioactivate to highly reactive
dehydropyrrolizidine alkaloids that react with nucleophilic groups of DNA
and proteins (Röder, 1995).
Many insects feed on pyrrolizidine-containing plants, although
pyrrolizidines are toxic. Numerous moths and butteries (Lepidoptera)
and some Chrysomelid leaf beetles (Coleoptera) can even sequester
pyrrolizidine alkaloids as defense compounds against predators. A behavior
called pharmacophagy in some adult members of the Lepidoptera makes
them selectively consume plants with pyrrolizidines (Boppre, 1990).
Free bases take up the reduced N-oxides in the gut of adapted
Lepidoptera. They are detoxied by oxidation, in the hemolymph, to the
water-soluble N-oxides, which do not act as substrates for bioactivation
cytochrome P450 enzymes. Pyrrolizidine alkaloids also play a signicant
role in the mating process, in addition to their function in chemical defense in
adapted butteries. Male moths synthesize the pheromone hydroxydanaidal
using pyrrolizidines to signal their alkaloid load to the females. Male moths
of the species Utetheisa ornatrix, during courtship, transfer sequestered
pyrrolizidine alkaloids as a nuptial gift to the female. The female moth gives
her alkaloids and pyrrolizidines taken up during mating to the egg mass to
protect the offspring (Eisner and Meinwald, 1995).
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1.2.7. Quinolizidine Alkaloids
Biosynthesis of Quinolizidine alkaloids takes place via cadaverine from
lysine. Most other compounds of this group are tri- or tetracyclic, apart
from the bicyclic lupinine. Figure 1.7 shows some representative structures.
Mostly quinolizidine alkaloids are present in the Fabaceae, but also in
numerous unrelated taxa, e.g., Ranunculaceae, Berberidaceae, Rubiaceae,
Chenopodiaceae, and Solanaceae (Wink, 2002). In elicited cell cultures of
species, traces of quinolizidines were found which usually do not synthesize
these metabolites (Wink and Witte, 1983). These results, along with the
occurrence of the quinolizidines alkaloids in taxonomically unrelated
species have generated a hypothesis that the genes for the biosynthesis
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Natural Compounds: An Introduction
of quinolizidines are extensively distributed in the kingdom of plants, but
are actively recorded only in a few species that utilize them as nourishing
deterrents against herbivores.
In the example of the sweet lupins, an alkaloid-free breeding form
the function of quinolizidines as defense compounds can be seen. Sweet
lupin, in contrast to the alkaloid-containing wild form, the bitter lupin is
more vulnerable to herbivores (Wink, 2003). Moreover, a minor function of
quinolizidines is nitrogen transport, in addition to their function as defense
compounds, in the phloem and probably storage of nitrogen in seeds (Wink
and Witte, 1984, 1985).
Hypotensive, antiarrhythmic, hypoglycemic, and CNS depressant effects
have been observed by the use of quinolizidines. Their pharmacological
properties such as toxicity can be dened through the interaction with
muscarinic and nicotinic receptors and inhibition of K
+
and Na+ channels.
Sparteine from broom (Cytisus scoparius) is utilized as antiarrhythmic.
However, about 10% of all patients who are unable to metabolize this
alkaloid suffer from intoxication, hence, its medicinal use is declining and
restricted (Wink, 2003).
Figure 1.7: Four representative structures of quinolizidine alkaloids.
Source: https://www.researchgate.net/gure/Four-representative-structures-ofquinolizidine-alkaloids_g6_226934227.
Adaptation to quinolizidine alkaloids and their sequestering as defense
compounds have only been observed in few insects, e.g., some larvae and
aphids of the pyralid moth Uresiphita reversalis (Wink and Witte, 1991;
Montllor et al., 1990). In contrast to pyrrolizidines, it is not used by a large
number of beetles and butteries.
1.2.8. Amaryllidaceae Alkaloids
The Amaryllidaceae alkaloids are limited to the monocot family that invented
their name. They are derivatives of the molecules of protocatechuic and
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tyrosine aldehyde, which have their origin from phenylalanine. Norbelladine
is the central intermediate of their biosynthetic path. About 500 structures
of Amaryllidaceae alkaloids have been identified, and some of them have
important pharmacological activities (Jin, 2007) (Figure 1.8). For instance,
narciclasine from Narcissus species and the isocarbostyrils pancratistatin
from the spider lily (Hymenocallis littoralis) signify auspicious antineoplastic
properties (Dumont et al., 2007; McLachlan et al., 2005). Lycorine has an
antiviral activity that is present in Crinum, Galanthus, and Clivia species
(Ieven et al., 1983; Szlávik et al., 2004).
Galanthamine has already found its application in medicine which is the
only alkaloid of this class. For the symptomatic treatment of Alzheimer’s
disease (AD), it has been approved in the United States and Europe. Reversible
and competitive inhibition of acetylcholinesterase (AChE) is its mode of
action, which causes the enhanced concentration of acetylcholine at neuronal
synapses. Moreover, on nicotinic acetylcholine receptors, galanthamine
acts as an allosteric modulator. Since the loss of acetylcholinergic neurons
concomitant with decreased levels of acetylcholine is the characteristic
feature of AD, galanthamine can, at least partially, enhance cognitive
functions in Alzheimer’s patients, and thus, compensate for the damage.
In the early 1950s, galanthamine was isolated rst from the Caucasian
snowdrop (Galanthus woronowii. During the Cold War, most of the
early studies on galanthamine was held in USSR and Bulgaria. At rst,
galanthamine was utilized for the treatment of post-polio paralysis and to
reverse neuromuscular blockade brought by muscle relaxants. The interest
in this drug increased after the discovery of the fact that galanthamine passes
the blood-brain barrier, and ultimately developed as a treatment for AD
(Heinrich, 2004).
Galanthamine is present in the bulbs of Leucojum, Narcissus, and
Galanthus, where it gathers in concentrations of 0.050% to 02% (Dewick,
2002). At rst, it was separated from these plant species. An economic and
feasible protocol for the industrial synthesis of galanthamine was developed
in 1999 by the groups of Jordis and Fröhlich in coordination with Sanochemia
(Küenburg et al., 1999).
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Figure 1.8: Example structures of Amaryllidaceae alkaloids.
Natural Compounds: An Introduction
Source: https://www.researchgate.net/gure/Chemical-structures-of-Amaryllidaceae-alkaloids-mentioned-in-the-text-illustrating-some_g4_237004105.
1.2.9. Monoterpene Indole Alkaloids (MIAs)
Biosynthesis of this class of alkaloids takes place from secologanin and
tryptophan through the central intermediate 3-α (S)-strictosidine. Over 2,000
structurally varied monoterpene indole alkaloids (MIAs) are identified, and
among them are numerous pharmacologically useful compounds (O’Connor
and Maresh, 2006). Figure 1.9 shows some major structures of the main
classes of MIAs. These alkaloids are normally found in the plant families of
Nyssaceae, Apocynaceae, Rubiaceae, and Loganiaceae.
One of the most signicant MIA today is the Catharanthus roseous
(C. roseous) which is known as the only source for the low-abundance
anti-tumor agents vinblastine and vincristine (VCR). C. roseous is highly
valued and has been studied extensively as a model for medicinal plants
improvement. The biosynthesis of these monoterpenoid indole alkaloids
(MIAs) is a complex multistep enzymatic network that is tightly regulated
by developmental and environmental factors (Pan et al., 2015).
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Figure 1.9: Different classes of monoterpene indole alkaloids.
Source: https://www.semanticscholar.org/paper/Chemistry-and-biology-ofmonoterpene-indole-O%E2%80%99Connor-Maresh/992ee4b9bf6bf2157d624
0d57678eb4d308aaeaa/gure/3.
1.2.10. camptothecin
Quinoline class of the MIAs have the origin of the Camptothecin (Figure
1.9). Feeding researches proved that it originates from monoterpene and
tryptamine precursor, although it lacks the indole ring, and the indole structure
experiences reorganizations to a quinoline heterocycle (Hutchinson et al.,
1974; Sheriha and Rapoport, 1976). Several unrelated eudicot species, e.g.,
Ervatamia heyneana (Apocynaceae), Camptotheca acuminate (Nyssaceae),
Nothapodytes foetida (Icacinaceae), and Ophiorrhiza pumila (Rubiaceae),
contain this alkaloid. In the mechanism of activity, the camptothecin is
unique. It binds the complex of covalently attached DNA and topoisomerase
I and stabilizes it (Hsiang et al., 1985). The replication fork is arrested
by this nondegradable topoisomerase/DNA I complex and hence kills
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cells by inhibiting the synthesis of DNA (Hsiang et al., 1989). Therefore,
camptothecin and its derivatives are also called topoisomerase “poisons.”
(Wall et al., 1966), a tree native to Tibet and China, also called “Happy
Tree” (Chinese “xi shu”). The reduced solubility of the alkaloid, despite
the auspicious anticancer activities, provided a major obstacle to clinical
application. By opening the lactone ring, derivatives soluble in water
were prepared. However, it became evident during the clinical trials that
the anticancer activity of these analogs was highly reduced, and the trials
were abandoned. It was discovered later on that the anticancer activity of
camptothecin was reliant on the intact lactone ring. In 1985, the research
in camptothecin returned after its exclusive mechanism of action became
known. The synthesis of water-soluble analogs was encouraged afterward
that retained the activity. At present, in cancer chemotherapy, two derivatives
of camptothecin are used. To treat colon cancer Irinotecan (syn. CPT-11) is
used with other chemotherapeutics, and for therapy of ovarian and smallcell lung cancer, topotecan is approved. In clinical trials, several new
camptothecin derivatives are recently tested (Sirikantaramas et al., 2007).
foetida, camptothecin derivatives are produced semi-synthetically. There are
alternatives to this limited resource. For instance, High levels of alkaloids
(4–5 mg/g dry weight) can be accumulated by young leaves of C. acuminate
(López-Meyer et al., 1994) and without killing the trees, they can be
harvested repeatedly. Moreover, bud culture of C. acuminata (Vincent et al.,
1997) and the clonal propagation of elite cultivars by shoot or hairy roots of
Ophiorrhiza pumila (Sudo et al., 2002) can provide an alternative solution
to overcome the deciency in plant material. Recently, in the endophytic
fungi, Entrophospora infrequent of N. foetida, camptothecin production was
observed (Puri et al., 2005; Amna et al., 2006), and a new source of synthesis
of the antineoplastic alkaloid can be open up by this method.
Natural Compounds: An Introduction
In 1966, camptothecin was isolated from Camptotheca acuminate
Using the alkaloids extracted from intact plants of C. acuminate or N.
1.3. NATURAL PRODUCTS DERIVED FROM THE
SHIKIMATE PATHWAY AND PHENYLPROPANOIDS
The precursors for phenylpropanoid compounds and benzoic acid
derivatives in plants can be provided by the shikimate pathway (Figure
1.10). Biosynthesis of shikimate takes place from phosphoenolpyruvate
and D-erythrose-4-phosphate, two metabolites that are derivatives of
the glycolysis and the pentose phosphate cycle respectively. By the
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addition of a C3, shikimate is further transformed to chorismate from
phosphoenolpyruvate; and chorismate aids as a precursor of the aromatic
amino L-tyrosine, L-phenylalanine, and L-tryptophan.
5-dehydroshikimate, an intermediate of the shikimate pathway, is the
precursor of the gallotannins and gallic acid (Werner et al., 1997), with several
molecules of gallic acid, these are esters of glucose. For the preparation of ink
from oak gall extract ferrous sulfate and for the tanning of hides, gallotannins
have been used for centuries. L-tyrosine, L-phenylalanine, and L-tryptophan are
necessary for animals and have to be consumed with food since the shikimate
pathway happens only in microorganisms and plants. The precursors of the
phenylpropanoids are L-tyrosine in monocots and L-Phenylalanine. This form
consists of phenylpropenes, lignin, coumarins, cinnamic acid derivatives,
and lignans, which all have the basic C
skeleton. Aromatic compounds,
6-C3
phenylpropanoids often have a hydroxyl group in the para-position. If at the
aromatic ring, more than one hydroxyl groups are present, the new hydroxyl
function is typically situated afterward the rst hydroxy group (ortho position).
Phenylpropanoids will be discussed together with the polyketides with extra
carbons derived from acetate units, e.g., the avonoids.
Figure 1.10: Schematic overview of shikimate and phenylpropanoid biosynthesis. Arrows with dashed lines indicate multiple biosynthetic reactions. Boxed
compounds are phenylpropanoids.
Source: https://www.researchgate.net/gure/Schematic-overview-of-shikimateand-phenylpropanoid-biosynthesis-Arrows-with-dashed_g4_226934227.
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Natural Compounds: An Introduction
1.3.1. Lignans and Lignins
Lignins and lignans are both made of coniferyl alcohol, hydroxycinnamic
alcohols (monolignols) p-coumaryl alcohol, and sinapyl alcohol (Figure
1.11). Lignins are polymers of monolignols and stereoselective coupling of
two hydroxycinnamic alcohols units from the lignans.
Coniferyl alcohol, the hydroxycinnamic alcohols (monolignols)
p-coumaryl alcohol, and sinapyl alcohol, after integration into the polymer
lignin, are also mentioned as G (guaiacyl), H (p-hydroxyphenyl), and S
(syringyl) units, respectively.
Low levels of H units and mainly G units form Lignin from gymnosperms.
Monocots and eudicots use all three monolignols, although lignin from
eudicots contains mostly S and G units (Boerjan et al., 2003).
Figure 1.11: p-Coumaryl alcohol, coniferyl alcohol, and sinapyl alcohol are the
building blocks of lignins and lignans.
Source: https://www.researchgate.net/gure/p-Coumaryl-alcohol-coniferylalcohol-and-sinapyl-alcohol_g5_257207765.
It became clear recently that also other phenolic monomers, especially
acylated monolignols, are integrated into lignin. The alcohols are associated
with various bonds, in the lignin polymer consisting of carbon-to-carbon
linkages and ether. Moreover, lignin can be connected with hemicelluloses
of the cell wall (Sun et al., 2005). The exact structure of the lignins has not
yet been explained due to the complexity and large size of the polymers,
although the monolignol composition of lignins can be determined (Davin
and Lewis, 2005). Together with the sugar polymers hemicellulose and
cellulose, the function of lignin is to strengthen the cell walls. To reinforce
the vascular tissue, lignication of cell walls is essential and emerged in
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