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PREFACE
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A natural product or compound is a chemical substance manufactured by a living
organism, i.e., it is only obtained from natural sources. Natural compounds can also
be synthesized in the laboratory by chemical preparation methods. The development
of products using chemical routes has played a crucial role in the growth of organic
chemistry by offering exciting synthetic domains. Presently, dietary supplements,
cosmetics, and food items synthesized from natural sources are also being referred to
as natural products.
In organic chemistry, natural products are an amalgam of organic compounds extracted
from natural sources involving primary and secondary metabolism. Within the area
of medicinal chemistry, the emphasis is only given to the compounds produced by
secondary metabolism. Various secondary metabolites are also considered to be
cytotoxic, which makes them a candidate for use as chemical agents against competing
organisms and predators. Presently, natural compounds are being explored extensively
for applications in different areas of human life, including drug delivery, cosmetics,
food packaging, pharmaceuticals, etc.
Compounds extracted from nature have always been identified to possess the
pharmaceutical potential and biological profiles far better than man-made materials.
However, natural compounds are extremely challenging to isolate and synthesize. For
instance, the strict requirements of the medical and pharmaceutical industries make the
extraction path of natural products a laborious journey.
This book is an introductory text intended to benefit the current and future generations
of motivated students looking for a practical understanding of compound isolation,
extract fractionation, structure elucidation, and determination of pharmacological
characteristics. The book is divided into eight chapters. Each chapter of the book
comprehensively discusses a particular topic related to natural compounds. Chapter
1 provides an introductory overview of the natural compounds with emphasis on
major categories of the compounds. Chapter 2 introduces the readers to fundamental
techniques used to extract the natural compounds from natural sources.
Chapter 3 provides a detailed analysis of a natural compound known as Alkaloids.
Different types, synthesis routes, and applications of alkaloids are discussed in the
chapter. Chapter 4 offers a brief introduction to flavonoids. Different categories of
flavonoids, their synthesis methods, and potential application areas are also discussed in
the chapter. Ecdysteroids are a bunch of natural polyhydroxysteroids present in animals
and plants. Chapter 5 focuses on the phytochemistry, pharmacology, and applications
of phytoecdysteroids.
Triterpenes are some of the most prolific natural products, including over 30,000
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structures found so far. Chapter 6 contains information about the bioavailability of
triterpenes along with a brief discussion about in-vivo and in-vitro studies. Presently,
new drug delivery methods are utilizing compounds with suitable activity at a greater
rate. Chapter 7 discusses the fundamentals of drug delivery systems and the applicability
of natural compounds in drug delivery systems. Finally, Chapter 8 briefly discusses the
use of natural compounds in food preservation and food packaging systems.
This book is primarily intended for students studying the chemistry and biology of
natural compounds and their potential applications. However, the book is equally
beneficial for people from diverse industrial backgrounds including food chemists,
biologists, chemists, environmentalists, governments, etc.
—Author
xx
CHAPTER 1
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INTRODUCTION TO FUNDAMENTAL
NATURAL COMPOUNDS
CONTENTS
1.1. Introduction ........................................................................................ 2
1.2. Nitrogen-Containing Natural Products ................................................2
1.3. Natural Products Derived from the Shikimate Pathway
and Phenylpropanoids ...................................................................16
1.4. Terpenoids ........................................................................................24
References ...............................................................................................37
2
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Natural Compounds: An Introduction
1.1. INTRODUCTION
A large number of natural products are produced by plants with greatly
diverse structures. Contrary to the “primary metabolites,” these products
are usually named “secondary metabolites” which are necessary for the
development and growth of plants. Initially, secondary metabolites were
officially considered as “waste products” having no physiological function
for the plant. However, with the advent of the chemical ecology about 30
years ago, it became clear that these products meet the significant requirement
of interaction between plants and their abiotic and biotic environment.
For instance, they can act as defense compounds against pathogens and
herbivores, as signal molecules or hormones for flower pigments that
attract pollinators. These products also have an important impact on human
culture in addition to their physiological function in plants and have been
used throughout the history of human beings as pigments, condiments, and
pharmaceuticals (Askitopoulou et al., 2000; Adam et al., 2002).
An overview of the diversity of secondary metabolites in plants has been
presented in this chapter, along with that their multi-faceted cultural history
and multiple biological functions have also been given. According to their
biosynthetic origin, these compounds are divided into four different groups:
phenylpropanoids, terpenoids, alkaloids, and polyketides. Only a limited
number of compounds and groups are presented since more than 200,000
structures of natural products from plants are known (Atkinson et al., 1991,
2000).
1.2. NITROGEN-CONTAINING NATURAL PRODUCTS
The Arabic word “al-qali” is the origin of the term alkaloid which denoted the
ashes containing potassium carbonate from plant material. Conventionally,
heterocyclic nitrogen compounds which are biosynthesized from amino
acids are termed alkaloids. However, several other substances that do not
concede to this rule are still acknowledged as alkaloids, primarily due to their
historical reasons or because of their bioactivities (Boonen and Häberlein,
1998; Baur et al., 2006). Presently, alkaloids having more than 12,000 known
structures, are considered one of the biggest groups of natural products.
This large number and vast structural diversity make it difficult and almost
impossible to provide a detailed summary of all types of alkaloids, and only
some major classes will be introduced. Glucosinolates, benzoxazinoids, and
cyanogenic glucosides will also be given in addition to the alkaloids. Similar
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to alkaloids, nitrogen is present in these metabolites and is derived from
amino acids (Barron and Ibrahim, 1996; Aziz et al., 2000).
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1.2.1. Purine Alkaloids
Nitrogen-containing compounds that originated from nucleoside metabolism
are termed Purine alkaloids (Ashihara and Crozier, 2001). A large number
of small molecules of primary metabolism synthesize the purine backbone,
including L-glutamine, L-aspartic acid, formate, and L-glycine. Plant
hormones or phytohormones-Cytokinins, that control apical dominance,
stem growth, and differentiation and senescence are derived from a similar
pathway. Several taxonomically unrelated plant species contain purine
alkaloids, e.g., tea (Camellia sinensis, Theaceae), coffee (Coffea arabica and
other Coffea species, Rubiaceae), coffee (Coffea arabica and other Coffea
species, Rubiaceae), cola (Cola nitida, Sterculiaceae), cacao (Theobroma
cacao, Sterculiaceae), and guaraná (Paullinia cupana, Sapindaceae).
Caffeine is the most abundant purine alkaloid, followed by theobromine and
some other purines, e.g., paraxanthine, and theophylline (Figure 1.1). Young
tea leaves contain ca. 2–3% caffeine, coffee seeds (“beans”) 1% (Ashihara
and Suzuki, 2004).
The function of caffeine in plants has been studied since it is accumulated
in higher quantities than any other purines. It may act as autotoxin (Friedmann
and Waller, 1985), and defense against herbivores (Hollingsworth et al.,
2002) as it inhibits the germination of coffee seedlings.
Caffeine acts as a central stimulant and is excessively consumed in
beverages like tea, coffee, and sodas, but also analgesics and medicine.
Adults consume about 280 mg of caffeine daily; one cup of black tea
contains ca. 80 mg caffeine, one cup of lter coffee contains ca. 140 mg
caffeine (Lovett, 2005). Theophylline is also of interest, besides caffeine,
due to its bronchodilatory effect, since it has been found in the therapy of
asthma (Botta et al., 2005).
The blockade of adenosine receptors is the main mode of action of
caffeine and other purine alkaloids, causing the release of neurotransmitters
(Fredholm, 1999). Phosphodiesterase enzyme that hydrolyzes the second
messenger cAMP, in higher concentrations is inhibited. However, by
utilization of caffeine-containing beverages, these blood concentrations are
commonly not reached. More recently, coffee drinkers show a reduced risk
for Parkinson’s disease which has increased the attention towards caffeine
(Ascherio et al., 2004; Alasmari, 2020).
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Natural Compounds: An Introduction
Ethiopia is the origin of Carabica, where nomads used to have fruits as
their food. Around 1000 AD, in Arabia, roasted coffee seeds (“beans”)
were brewed to prepare a drink named “qahwah,” and after 1600 AD, it
was introduced into Europe as “kahveh.” Then coffee and coffee houses
became popular in Europe. At the start of the 18
th
century, a text written by
Picander, Johann Sebastian Bach’s “Coffee Cantata” (BMV 211), indicates
this expanding popularity along with controversy on the anticipated harmful
health effects of coffee at that time (Bravo and Lazo, 1993, 1996).
Tea is made from unfermented (green tea), dried leaves of C. Sinensis, or
fermented (black tea). In the rst millennium BC, the earliest records on tea
drinking come from China. After that, in the 8
th
century, it was introduced
to Japan by Buddhist monks. The Dutch East India Company in 1606 rst
shipped tea to Europe.
The Amazon Basin marks the origin of the cacao tree (T. cacao,
Sterculiaceae), but it was produced in Mesoamerica by the Mayas. Caffeine
and theobromine are present in its seeds (“beans”). Roasted cacao seeds
along with chili peppers and other spices were used by Aztecs and Mayans
to prepare a drink, which was called “xocoatl” by the Aztecs (Colombo et al.,
2012). According to the belief of Aztecs, their god Quetzalcoatl has given
cocoa to humanity. The cacao tree was named after the Aztec tradition by
the Swedish botanist Carl Linnaeus; Theobroma means “food of the gods”
in Greek. The Spanish Conquistador Hernán Cortés rst brought the cocoa
beans into Europe (Chou et al., 1980; Briskin, 2000).
Figure 1.1: Structures of the purine alkaloids caffeine, theobromine, theophylline, and paraxanthine.
Source: https://www.researchgate.net/gure/Chemical-structure-of-methylxanthines-caffeine-theobromine-theophylline-and_g1_267755266.
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5
1.2.2. Tropane Alkaloids
Amino acids arginine and/or ornithine are the origins of tropane alkaloids.
The bicyclic tropane skeleton common in all of them, consists of a sevenmembered ring with an N-bridge between C-5 and C-1, the nitrogen being
methylated. Nortropanes lacking the seco-tropanes and N-methylation with
a dismembered N-bridge have been defined, too (Griffin and Lin, 2000).
Numerous tropane alkaloids are esters of the alcohols pseudotropine
(tropane-3 b-ol) or tropine (tropane-3 a-ol) (Figure 1.2) with aromatic
or aliphatic acids. First, the tropane alkaloids were separated from the
nightshade family (Solanaceae).
Figure 1.2: Tropane amino alcohols.
Source: https://www.researchgate.net/gure/Tropane-alkaloid-biosynthesis-aTropinone-reductase-form-a-branch-point-in-the-pathway_g1_232720949.
In the related family Convolvulaceae, numerous structurally varied
tropanes, however, have been discovered, like a member of the order
Solanales, the Solanaceae, and in some species from the unrelated plant
families Erythroxylaceae, Brassicaceae, Proteaceae, Euphorbiaceae, and
Rhizophoraceae (Grifn and Lin, 2000).
1.2.3. Hyoscyamine and Scopolamine
(S)-Scopolamine and (S)-Hyoscyamine are esters of the amino alcohols
scopine and tropine with (S)-tropic acid, which is a derivative of phenylalanine
(Figure 1.3). Solanaceae family exclusively contains these two alkaloids.
They can lead to the relaxation of smooth muscles and increase in pulse
rate as they can act as antagonists of muscarinic acetylcholine receptors
(parasympatholytics), e.g., in the bronchial tract and gastrointestinal,
reduction of bronchial, sweat gland, salivary, and gastric secretion. While
scopolamine depresses the central nervous system (CNS), hyoscyamine is a
CNS stimulant (Bruce-Chwatt, 1988; Didry et al., 1994).
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Natural Compounds: An Introduction
During the extraction of plant material, Atropine, the (R)-hyoscyamine, and
the racemate of (S)-are formed. Although the (R)-enantiomer is less effective
than (S)-hyoscyamine, atropine is mostly used for traditional reasons. In
medicine, during biliary colic, atropine is used against spasms as an antidote
against intoxication with organophosphorus insecticides, and before surgery
as pre-medication to decrease respiratory and salivation secretion. (S)Scopolamine is also used as a medication for motion sickness. Derivatives
of scopolamine or hyoscyamine are used as a treatment for asthma and
chronic obstructive bronchitis, mydriatics for eye examinations, and against
gastrointestinal spasms (Drawert and Beier, 1976; Dixon and Paiva, 1995).
Figure 1.3: The tropane alkaloids (S)-hyoscyamine and (S)-scopolamine occur
only in the Solanaceae family.
Source: https://www.mdpi.com/1420-3049/24/4/796/htm.
Plants containing scopolamine and hyoscyamine have widely used
throughout history as psychoactive, poisons, drugs, and for the preparation
of sleeping potions and analgesic. Well-known examples include thorn-apple
(Datura species), mandrake (Mandragora ofcinarum), deadly nightshade
(Atropa belladonna), henbane (Hyoscyamus niger). All these plants are toxic
and, for instance, 5 to 10 fruits of A. belladonna are deadly in an adult. This
is indicated in the name of “Atropa,” the Greek goddess of destiny who cuts
the thread of life. The custom of Renaissance ladies who dilated their pupils
with extracts of the deadly nightshade is referred to as “Belladonna” (Italian
for “beautiful woman”). In literature, Solanaceous plants with tropanes are
frequently mentioned, in several pieces by William Shakespeare and in
Homer’s Odyssey (Fahey et al., 2001; Duffy et al., 2007).
(S)-hyoscyamine was extracted from H. niger (Geiger and Hesse, 1833)
after Atropine was isolated from A. belladonna (Mein, 1833). Schmidt
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7
(1892); and Ladenburg (1881) detected the (S)-scopolamine in the late
th
century. Today, Duboisia myoporoides and Duboisia leichhardtii are
19
sources of (S)-scopolamine and (S)–hyoscyamine, a tree native to Australia,
and hybrids of the two species.
1.2.4. Cocaine
Benzoic acid ester of the tropane base methyl ecgonine is termed Cocaine.
Only Erythroxylum novogranatense and Erythroxylum coca small trees
or shrubs native to the Andes contain considerable amounts of cocaine in
their leaves, i.e., up to 1% of their dry mass (Plowman and Rivier, 1983).
The cocaine content declines rapidly if the coca leaves are dried or stored
inappropriately. There are also other ecgonine derivatives, in the two
Erythroxylum species, e.g., the truxillins and cis- and trans-cinnamoylcocaine,
esters of methylecgonine with dimeric cinnamic acid (Figure 1.4) (Griffin
and Lin, 2000).
Cocaine is a highly addictive CNS stimulant that inhibits the reuptake of the norepinephrine and neurotransmitters at synapses, and
inhibits the enzyme monoamine that degrades epinephrine, dopamine, and
norepinephrine.
Figure 1.4: Erythroxylum alkaloids.
Source: https://link.springer.com/chapter/10.1007/978-0-387-85498-4_1.
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Natural Compounds: An Introduction
This can cause hyperactivity, suppression of hunger, euphoria, and fatigue.
Dilation of pupils, increase blood pressure and heart rate, hyperthermia,
and hyperglycemia are the peripheral effects of cocaine (White and Lambe,
2003; White, 2003). Cocaine blocks Na
+
channels if applied on mucous
membranes leading to local anesthesia. Hence, in surgeries of ear, nose,
eyes, and throat, cocaine is used as a local anesthetic.
Cocaine is a primary commodity present in illegal drugs. The
hydrochloride can be chewed, sniffed, and injected and is soluble in
water. Extraction of cocaine from alkaline solutions with ether produces
a “Freebase” cocaine base. It can be inhaled by smoking and evaporates
at high temperatures. Crack is another smokable form of cocaine, which is
produced by the precipitation of cocaine hydrochloride from a solution with
baking soda (Field et al., 2001; Frick et al., 2005).
The chewing of coca leaves in South America has been a long tradition
and ages back to 3000 B.C. This is used to overcome thirst, hunger,
exhaustion, and does not have the addictive potential of cocaine. An alkaline
agent like sodium bicarbonate and plant ash is used along with the chewing
of cocaine, which transforms the alkaloids to their free base. Only a tiny
portion of the cocaine is hydrolyzed to methyl ecgonine (Rivier, 1981).
The Spanish conquistadores brought coca leaves to Europe, and in the
1860s, cocaine was isolated from the leaves. The French chemist Angelo
Mariani, in 1863, created the tonic “Vin Mariani,” which is an extract of coca
in Bordeaux wine. American Pharmacist John Pemberton 1886 invented the
non-alcoholic version “Coca-Cola,” which mixed extracts of coca leaves
and caffeine-containing cola nuts with soda. In 1906, with the introduction
of the rst anti-drug laws in the USA, however, for the production of Coca-
Cola only decocainized leaves were used (Fujii and Ohba, 1998).
1.2.5. Calystegines
Nortropane skeleton is present in cysteines with three to five hydroxyl
groups. The hydroxyl groups are not esterified, in contrast to most other
tropane alkaloids, but they can be glycosylated. Only in calystegine N, the
bridgehead C-1 of calystegines is hydroxylated and is linked to an amino
group instead (Dräger, 2004); Figure 1.5 shows the structure of the three
most widely used calystegines. The first structures of calystegines were
determined in 1990 (Goldmann et al., 1990) after its discovery in roots of
Calystegia sepium (Tepfer et al., 1988). Since then, they have been separated
from several members of Convolvulaceae, Solanaceae, Brassicaceae,
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