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© Springer Nature Singapore Pte Ltd. 2020
M. K. Swamy (ed.), Plant-derived Bioactives,
https://doi.org/10.1007/978-981-15-2361-8_5
E. P. Gutiérrez-Grijalva · L. X. López-Martínez
Cátedras CONACYT-Centro de Investigación en Alimentación y Desarrollo,
Culiacán, Sinaloa, Mexico
L. A. Contreras-Angulo · C. A. Elizalde-Romero · J. B. Heredia (*)
Centro de Investigación en Alimentación y Desarrollo, Culiacán, Sinaloa, Mexico
e-mail: jbheredia@ciad.mx
5
Plant Alkaloids: Structures andBioactive
Properties
ErickPaulGutiérrez-Grijalva, LeticiaXochitlLópez-
Martínez, LauraAracelyContreras-Angulo,
CristinaAliciaElizalde-Romero, andJoséBasilioHeredia
Contents
5.1 Introduction 86
5.2 Classication of Plant Alkaloids 89
5.2.1 True Alkaloids (Heterocyclics) 90
5.2.1.1 Pyrrole Alkaloids 90
5.2.1.2 Pyrrolidine Alkaloids 90
5.2.1.3 Pyrrolizidine Alkaloids 91
5.2.1.4 Pyridine Alkaloids 91
5.2.1.5 Piperidine Alkaloids 92
5.2.1.6 Quinoline Alkaloids 92
5.2.1.7 Tropane Alkaloids 92
5.2.1.8 Isoquinoline Alkaloids 92
5.2.1.9 Aporphine Alkaloids 93
5.2.1.10 Quinolizidine Alkaloids 93
5.2.1.11 Indole Alkaloids 93
5.2.1.12 Indolizidine Alkaloids 94
5.2.1.13 Imidazole Alkaloids 94
5.2.2 Protoalkaloids (Non-heterocyclics) 94
5.2.3 Pseudoalkaloids 95
5.3 Plant Sources of Alkaloids 95
5.3.1 The Amaryllidaceae Family 95
5.3.2 The Apocynaceae Family 96
5.3.3 The Papaveraceae Family 97
5.3.4 The Asteraceae Family 97
5.3.5 The Solanaceae Family 98
5.3.6 The Rutaceae Family 98
86
5.3.7 The Fabaceae Family 99
5.3.8 The Rubiaceae Family 99
5.4 Bioactive Properties of Plant Alkaloids 101
5.4.1 Anticancer Properties of Plant Alkaloids 102
5.4.2 Antidiabetic Properties of Plant Alkaloids 104
5.4.3 Plant Alkaloids and Alzheimer’s Disease 106
5.5 Conclusion and Future Perspectives 108
References 108
Abstract
Alkaloids are nitrogen-containing natural products found in bacteria, fungi, ani-
mals, and plants with complex and diverse structures. The widespread distribu-
tion of alkaloids along with their wide array of structures makes their classication
often difcult. However, for their study, alkaloids can be classied depending on
their chemical structure, biochemical origin, and/or natural origin. Alkaloids can
be derived from several biosynthetic pathways, such as the shikimate pathway;
the ornithine, lysine, and nicotinic acid pathway; the histidine and purine path-
way; and the terpenoid and polyketide pathway. Traditionally, plant alkaloids
have played a pivotal role in folk medicines since ancient times as purgatives,
antitussives, sedatives, and treatments for a wide variety of ailments. Currently,
several alkaloids have served as models for modern drugs, and there are several
alkaloids used in pharmacology, such as codeine, brucine, morphine, ephedrine,
and quinine. Herein, this work is a comprehensive revision from the Web of
Knowledge and Scopus databases on the recent information (2010–2019)
regarding plant-derived alkaloids, their structural classication and bioactive
properties.
Keywords
Alkaloids · Medicinal plants · Anticancer · Phytochemicals · Natural
compounds
5.1 Introduction
Plants are the source of many metabolites with different physiological functions.
Among the most studied metabolites are the phytochemicals, which are mainly sec-
ondary metabolites produced by plants that vary in structure, amount, location, and
activity even in plants from the same cultivar. These metabolites are often classied
into three major groups: phenolic compounds, terpenes, and nitrogen- and sulfur-
containing compounds (Mazid etal. 2011; Ncube etal. 2015). Alkaloids are a very
wide group of natural compounds derived from secondary metabolism, and their
main characteristic feature is the presence of a basic atom of nitrogen in any posi-
tion of the molecule (does not include nitrogen in an amide bond or peptide). They
are commonly isolated from plants; however, they have also been found in animals,
insects, marine invertebrates, and some microorganisms (Lu etal. 2012; Roberts
E. P. Gutiérrez-Grijalva et al.
87
2013; Bribi 2018). They can be present in different organs of the cell like mitochon-
dria, vesicles, chloroplasts, and vacuoles. Its precursors (mainly amino acids) are
derivatives of metabolic pathways, such as glycolysis. Figure5.1 exemplies how
the biosynthetic pathways are as diverse as the group of alkaloids, for example, the
aromatic amino acids phenylalanine, tyrosine, and tryptophan precursors of some
alkaloids, such as indole and isoquinoline alkaloids, derived from the shikimate
pathway (Wink 2010; O’Connor 2010; Aniszewski 2015).
These compounds are abundant in nature, i.e., they are found in at least 25% of
plants. They are generally produced to facilitate the survival of plants in the ecosys-
tem, because they are allelopathic compounds, i.e., they have the potential to be a
natural herbicide (Jing etal. 2014). Alkaloids are compounds that can be found in
plants, fungi, bacteria, and animals. Their function in plants is not entirely under-
stood, but it is highly related to seed formation and protection against predators.
Since alkaloid function is not exclusive to the organism producing it, their pharma-
cological properties have been highly studied (Mazid etal. 2011).
The term alkaloid was originally used to refer to base-type compounds that con-
tained nitrogen and react with acids forming salts. The word is derived from the
CO2
Citrate
Oxoglutarate
Succinate
Malate
Oxalacetate
Photosynthesis
Erithrose-4-phosphate
Phosphoenolpyruvate
Shikimate
Chorismate
Anthranilate
Prephenate
Arogenate L-TriptophanAcridone
alkaloids
Indole alkaloids
Isoquinole
alkaloids
L-Tyrosine L-Phenylalanine
Shikimate
pathway
Glyceraldehyde-3-
phosphate
Pyruvate
Acetyl-CoA
Terpenoids
alkaloids
IPP
DMAPP
Glycolysis
Malonyl-CoA
Polyketides
Glutamate
Glutamine Ornithine
Purines
alkaloids
Pyrrilizidine
alkaloids
Tropane alkaloids
Coca alkaloids
Nicotiana alkaloids
Arginine
Aspartate
Lysine
Piperidine alkaloids
Lupin alkaloids
Sedum alkaloids
Krebs
cycle
Conium
alkaloids
Glucose
Fig. 5.1 Metabolic pathway of alkaloid biosynthesis. Abbreviations: IPP isopentenyl diphos-
phate, DMAPP dimethylallyl diphosphate. Elaborated from data in Wink (2010)
5 Plant Alkaloids: Structures andBioactive Properties
88
word al-qali, with an Arabic origin. The study of this group of metabolites began in
1806, when morphine (Fig.5.2) was isolated from opium by Sertürner. Since then,
many plant extracts have been used as poisons and medicine, due to their alkaloid
content. Chemically they are dened as crystalline, colorless substances with bitter
taste that can form salts when being united to acids; in the plants, they can hide in
free state, like salts or like N-oxides (Kutchan 1995; O’Connor 2010; Amirkia and
Heinrich 2014; Encyclopædia Britannica 2018; Bribi 2018).
History shows us examples of renowned characters that used alkaloid-based
extracts, such as Socrates whose death was caused by Conium maculatum extract
and Cleopatra, who was known for using Hyoscyamus muticus to dilate her pupils
to achieve a more attractive appearance. In Medieval Europe, Atropa belladonna
was frequently used by women aiming for the same results as Cleopatra, being the
alkaloid, coniine (Fig.5.2), the responsible compound in this particular case. Later
on, in history, its derivatives began to be used during medical examinations for dilat-
ing pupils. Tropicamide is another similar example since it has been used for
Alzheimer’s disease diagnosis (Ncube etal. 2015). Nowadays, research has led to
identifying several types of alkaloids in over 4000 different plants. Some plant fami-
lies are known for their high content, such as the Papaveraceae, Ranunculaceae,
Solanaceae, and Amaryllidaceae families (Encyclopædia Britannica 2018).
Alkaloid classication, which will be further explained in this chapter, depends
on many characteristics, mainly chemical properties, taxonomy, and botanical and
pharmaceutical functions. The most used classication is given by the position of
nitrogen and whether if it’s part of the ring or not; in this regard, we can identify
heterocyclic alkaloids or typical alkaloids and non-heterocyclic or atypical alka-
loids (Evans 2009). Also, depending on their biosynthetic pathway, alkaloids can be
classied into terpenoid indole alkaloids, benzylisoquinoline alkaloids, tropane
alkaloids, and purine alkaloids (Facchini 2001).
Morphine structure. Adapted from PubChem
(National Center for Biotechnology Information 2019b)
Coniine structure. Adapted from PubChem
(National Center for Biotechnology Information 2019a)
Fig. 5.2 Chemical structure of morphine and coniine (National Center for Biotechnology
Information 2019a, b)
E. P. Gutiérrez-Grijalva et al.
89
Since ancient times, civilizations have used plants (root, leaf, stem, fruit, and seeds)
containing alkaloids as remedies (teas, poultices, potions, etc.) to treat some diseases
or as poison (Goyal 2013; Roberts 2013; Jing etal. 2014). The biological signicance
of alkaloids depends on their signicant relation with health benets. Alkaloids are
now medically known anesthetics, stimulants, antibacterials, antimalarials, analge-
sics, antihypertensive agents, spasmolysis agents, anticancer drugs, antiasthma thera-
peutics, vasodilators, antiarrhythmic agents, etc. These properties, as well as their
toxicity continue to be an important research eld (Kuete 2014).
5.2 Classification ofPlant Alkaloids
Currently, the Dictionary of Alkaloids reports more than 40,000 compounds
(Buckingham etal. 2010), andmany of them are named according to their origin,
that is to say the plant and botanical family from which they were isolated (Table5.1),
as well as can also be classied according to their origin (Talapatra and Talapatra
2015). Moreover, due to the wide diversity of alkaloids distributed in plants and the
lack of a taxonomic base to dene them consistently, their classication can also be
based on their natural or biochemical origin or their chemical structure, the latter
Table 5.1 Alkaloid classication according to their origins and sources
Alkaloids Plant Family References
Berberine Berberis asiatica Berberidaceae Mazumder etal. (2011).
Anonaine Annona squamosa Annonaceae Porwal and Kumar
(2015)
Morphine,
papaverine
Papaver somniferum Papaveraceae Baros etal. (2012)
Salsoline Salsola kali Amaranthaceae Boulaaba etal. (2019)
Thalfoliolosumine Thalictrum foliolosum Ranunculaceae Li etal. (2016)
Galanthamine Galanthus woronowii Amaryllidaceae Bozkurt etal. (2017)
Lycorine Amaryllis belladonna Amaryllidaceae Tallini etal. (2017)
Srilankine Alseodaphne
semecarpifolia
Lauraceae Thakur etal. (2012)
Vincristine,
vinblastine
Vinca rosea Apocynaceae Adewusi and Afolayan
(2010)
Lupanine Lupinus angustifolius Fabaceae Jansen etal. (2012)
Quinine Cinchona pubescens Rubiaceae Noriega etal. (2015)
Huperzine A Huperzia serrata Lycopodiaceae Ferreira etal. (2016)
Geissospermine Geissospermum vellosii Apocynaceae Mbeunkui etal. (2012)
Solanine Solanum melongena Solanaceae Friedman (2015)
Piperine Piper nigrum Piperaceae Li etal. (2011)
Atropine Atropa belladonna Solanaceae Koetz etal. (2017)
Cocaine Erythroxylum coca Erythroxylaceae Jirschitzka etal. (2012)
Nicotine Nicotiana tabacum Solanaceae Baranska etal. (2013)
Echimidine Echium hypertropicum Boraginaceae Carvalho etal. (2013)
Caffeine Camellia sinensis Theaceae Wang etal. (2011)
5 Plant Alkaloids: Structures andBioactive Properties
90
being the most used, and is based on its main structure,i.e., a CN skeleton (Cushnie
etal. 2014; Bribi 2018). In this regard, according to their molecular structure and
biosynthetic pathway, alkaloids can be divided into three different types: (a) true
alkaloids (heterocyclics), (b) protoalkaloids (non-heterocyclics), and (c) pseudoal-
kaloids (Ranjitha and Sudha 2015).
5.2.1 True Alkaloids (Heterocyclics)
They are chemically complex, physiologically active compounds, and derivatives of
cyclic amino acids.They have an intracyclic nitrogen, and can be found in nature
forming salts with some organic acids, such as oxalic, lactic, malic, tartaric, acetic,
and citric acid (Talapatra, Talapatra 2015; Henning 2013). The alkaloids of this
group are derivatives of the amino acids L-ornithine, L-tyrosine, L-phenylalanine,
L-lysine, L-histidine, L-tryptophan, L-arginine, and glycine/aspartic acid (Kukula-
Koch and Widelski 2017); these amino acids are the basis of a certain group of
alkaloids, for instance, tryptophan is the base of the indole, quinoline, and pyrro-
loindole alkaloids; the amino acid tyrosine is the basis of the isoquinoline alkaloids;
the amino acid ornithine for the tropane, pyrrolizidine, and pyrrolidine alkaloids;
and lysine for the quinolizidine and piperidine alkaloids; aspartate is the base for the
pyridine alkaloids; anthranilic acid is the precursor for quinazoline, quinoline, and
acridone alkaloids; and the derivatives of histidine are the imidazole alkaloids
(Böttger etal. 2018; Kaur etal. 2019; Aniszewski 2015). The heterocyclic alkaloids
are divided into pyrrole, pyrrolidine, pyrrolizidine, pyridine, piperidine, tropane,
quinolone, isoquinoline, aporphine, quinolizidine, indole, indolizidine, and imidaz-
ole (Fig.5.3). Within these groups, we can nd alkaloids, such as berberine, salso-
line, geissospermine, piperine, nicotine, lobeline, nantenine, cocaine, quinine,
dopamine, and morphine (Hussain etal. 2018).
5.2.1.1 Pyrrole Alkaloids
This is the most important group of heterocycle alkaloids, since they are present in
various natural and unnatural compounds with pharmacological properties. The
most commonly known pyrrole alkaloids are the derivatives of heme and chloro-
phyll. These compounds contain four groups of pyrrole joined by methine bridges
(Estévez etal. 2014). The pyrrole ring is the central nucleus of the carbazole alka-
loid structure, which can be found mostly in the Rutaceae family, within the genera
Murraya, Glycosmis, and Micromelum (Bauer and Knölker 2012).
5.2.1.2 Pyrrolidine Alkaloids
These types of alkaloids are derivatives of the amino acid L-ornithine, and in some
cases, they are derived from arginine and lysine with the addition of acetate/malo-
nate units; they contain rings in their structure. Some pyrrolidine alkaloid types are
putrescine, hygrine, and cuscohygrine (Kaur and Arora 2015) and can be found in
families such as Fabaceae, Erythroxylaceae, and Moraceae (Kukula-Koch and
Widelski 2017).
E. P. Gutiérrez-Grijalva et al.
91
5.2.1.3 Pyrrolizidine Alkaloids
More than 500 compounds have been identied as pyrrolizidine alkaloids, which are
derivatives of the amino acid ornithine. Pyrrolizidine alkaloids can be found in the
form of esters of 1-hydroxymethyl-1,2-dehydropyrrolizidine (necines) and may have
a hydroxyl group at position 7; however, the position C-2 and C-6 can be hydroxyl-
ated (Koleva etal. 2012; Schramm etal. 2019). They are characterized by having in
their structure two rings of ve members with an atom of nitrogen between them; a
double ligature in C-1 and C-2 determines the toxicity of this alkaloid. According to
its base, necines are divided into four groups: retronecine, heliotridine, otonecine,
and platynecine (Moreira etal. 2018). Pyrrolizidine alkaloids can be mainly found in
the families Asteraceae and Boraginaceae (Koleva etal. 2012).
5.2.1.4 Pyridine Alkaloids
These heterocyclic compounds contain in their nucleus an unsaturated nitrogen radi-
cal and are derivatives of the amino acid L-ornithine. Some common pyridine
H
N
H
N
N
H
N
N
N
NN
Pyrrole Pyrrolidine Pyridine Piperidine
Quinoline Isoquinoline Indolizidine
Tropane Indole Imidazole
SH
N
H
N
Fig. 5.3 Skeletal structure of true alkaloids (heterocyclics)
5 Plant Alkaloids: Structures andBioactive Properties
92
alkaloids are piperine, coniine, trigonelline, arecoline, arecaidine, guvacine, cytisine,
lobeline, nicotine, anabasine, sparteine, and pelletierine (Kaur and Arora 2015).
These alkaloids are present in the botanical families Aizoaceae, Annonaceae,
Apocynaceae, Araceae, Bignoniaceae, Dipsacaceae, Gramineae, Palmae, and
Umbelliferae, among others (Silva Teles etal. 2019).
5.2.1.5 Piperidine Alkaloids
They are widely studied, and about 700 compounds are known as piperidine alka-
loids. They are derivatives of L-lysine, and its structure contains a ring of six radi-
cals, ve groups of methylene, and one amine. In this group, we can nd the
alkaloids like solenopsin, cynapine, lobeline, and coniine. Piperidine alkaloids can
be found in plants of the family Lobeliaceae, particularly Lobelia inata, which
contains the alkaloid lobeline (Liu etal. 2010; Kaur, Arora 2015). We can also nd
them in black pepper (Piper nigrum) as piperine and in Punica granatum as pelle-
tierine. Likewise, there are numerous natural products that contain piperidine resi-
dues in their skeleton (Goel etal. 2018; Böttger etal. 2018).
5.2.1.6 Quinoline Alkaloids
This group of alkaloids derived from L-tryptophan is heterocyclic aromatic com-
pounds formed by the fusion of a benzene ring with a pyridine ring. Quinine is one
of the most important of this group and is found in Cinchona ledgeriana, while the
quinidine alkaloid is obtained from C. ofcinalis. Some other quinoline alkaloids
are pamaquine, chloroquine, tafenoquine, and bulaquine (Marella etal. 2013; Kaur
and Arora 2015; Debnath et al. 2018). The plants of the genus Melodinus are an
important source of these alkaloids, as well as those belonging to the Rutaceae fam-
ily (Byler etal. 2009; Cai etal. 2011).
5.2.1.7 Tropane Alkaloids
They are derivatives of the amino acid ornithine. Tropane alkaloids have a complex
structure and are characterized by their skeleton N-methyl-8-azabicyclo[3,2,1]
octane (Mao etal. 2014). More than 200 alkaloids can be classied as tropane alka-
loids, and these are mainly distributed in the angiosperms of different families, such
as Proteaceae, Solanaceae, Erythroxylaceae, Convolvulaceae, Brassicaceae, and
Euphorbiaceae (Jirschitzka etal. 2012). The most studied are found in the Solanaceae
family, mostly in the genera Datura (hyoscyamine and scopolamine), Hyoscyamus
(scopolamine), and Atropa (atropine alkaloid) (Ajungla etal. 2009; Wink 2010;
Guirimand et al. 2010). Another well-known tropane alkaloid is the cocaine,
obtained from Erythroxylum coca (Erythroxylaceae). Interestingly, 186 alkaloids
have been found only in this species (Oliveira etal. 2010; Jirschitzka etal. 2012).
Atropine is another common tropane alkaloid and is considered a basic drug list of
the World Health Organization (Ranjitha and Sudha 2015).
5.2.1.8 Isoquinoline Alkaloids
They are among the most abundant in the kingdom of plants; we can nd them in
the families Papaveraceae, Berberidaceae, Fumariaceae, Ranunculaceae, Rutaceae,
E. P. Gutiérrez-Grijalva et al.
93
Amarryllidaceae, and Annonaceae (Kukula-Koch and Widelski 2017). Isoquinoline
alkaloids are heterocyclic aromatic compounds derived from the amino acids tyro-
sine and phenylalanine, formed from 3,4-dihydroxytyramine (dopamine). According
to their structure, isoquinoline alkaloids can be divided into simple isoquinolines,
which have a benzene ring attached to a pyridine ring, and benzylisoquinolines,
which contain a second aromatic ring (Khan and Kumar 2015). Likewise because
they are a structurally non-homogeneous group and depend on the degree of oxy-
genation, intramolecular rearrangement, distribution, and the presence of additional
rings that are connected to the main system, these can be divided into subgroups
benzylquinoline, aporphine, protoberberine, benzo[c]phenanthridine, protopine,
phthalide isoquinoline, morphine, and emetine alkaloids (Bhadra and Kumar 2011;
Koleva etal. 2012; Kukula-Koch and Widelski 2017; Hussain etal. 2018). One of
the most known alkaloid is morphine, which is an isoquinoline alkaloid, and is
obtained from opium (Papaver somniferum). In this species, we also nd the alka-
loid codeine, a benzylisoquinoline alkaloid; berberine in Berberis aristata, B.
lyceum, and B. tinctoria; and colchicine in Colchicum autumnale (Baros etal. 2012;
Diamond and Desgagné-Penix 2016; Debnath etal. 2018).
5.2.1.9 Aporphine Alkaloids
Aporphine alkaloids are heterocyclic alkaloids derived from isoquinoline alkaloids.
These compounds have been isolated from approximately 100 genera and from
diverse families (approximately 20), such as Annonaceae, Menispermaceae,
Papaveraceae, Ranunculaceae, Lauraceae, Monimiaceae, Magnoliaceae, and
Berberidaceae, among others. Some common aporphine alkaloids are caaverine,
lirinidine, asimilobine, N-methyl-asimilobine, nornuciferine, nuciferine, anonaine,
magnoorine, dicentrine, boldine, galucine, and neolitsine. All of the aforemen-
tioned differ in the substituents in the position of the nitrogen atom; these can be -H,
-CH3, -COOH3, etc. (Chen etal. 2013; Muthna etal. 2013).
5.2.1.10 Quinolizidine Alkaloids
These compounds are derivatives of the amino acid L-lysine and are formed by the
fusion of two rings of six members that share a nitrogen atom, and its structural
variation goes from simple to complex. We can nd them mainly in the Leguminosae
family, especially in the genus Lupinus; however, they are also present in the genera
Baptisia, Thermopsis, Genista, Cystus, and Sophora. The most commonly known
quinolizidine alkaloids are lupanine (Lupinus luteus), cytisine (Laburnum species),
and sparteine alkaloids (Sarothamnus scoparius) (Bunsupa etal. 2012; Szőke etal.
2013; Kaur and Arora 2015).
5.2.1.11 Indole Alkaloids
They have a bicyclic structure, consisting of six-membered benzene ring fused to
a ve-membered nitrogen-containing pyrrole ring, the latter providing the property
of basicity, and its precursor is the amino acid tryptophan (Hamid etal. 2017).
There are approximately 2000 identied compounds known as indole alkaloids
distributed in different families such as Apocynaceae, Loganiaceae, Rubiaceae,
5 Plant Alkaloids: Structures andBioactive Properties
94
and Nyssaceae, as well as plant species such as Catharanthus roseus (vinblastine
and vincristine alkaloids), Rauvola serpentina (ajmalicine), Camptotheca acumi-
nata (camptothecin), Passiora incarnata (harman, harmol, harmine, harmaline),
Mitragyna speciosa (mitragynine), Rauwola serpentina (reserpine, serpentinine,
ajmaline, corynanthine, and yohimbine (Guirimand etal. 2010; Sagi etal. 2016;
Hamid etal. 2017).
5.2.1.12 Indolizidine Alkaloids
The precursor of indolizidine alkaloids is the amino acid L-lysine. Indolizidine
alkaloids are heterocyclic alkaloids, characterized by the fusion of six- and ve-
membered rings, with a nitrogen atom between ring fusions. They have been found
in different plants of the genus Ipomoea. Specically, the alkaloids like ipalbine,
ipalbidine, and isoipomine occur in I. alba (seeds). Among others, I. carnea pos-
sesses the alkaloid swainsonine, which is found in most of the plants of this genus;
however, it was initially isolated from plants of the genus Swainsona (Meira etal.
2012; Diaz 2015). The main indolizidine alkaloids are swainsonine, castanosper-
mine, and lentiginosine (Michael 2008).
5.2.1.13 Imidazole Alkaloids
These alkaloids are derived from L-histidine, and this group is comprised of the
alkaloids histamine, histidine, pilocarpine, and pilosine, obtained mainly from two
families Cactaceae and Rutaceae (Aniszewski 2015). Pilocarpine is the main imid-
azole alkaloid and was isolated from leaves of Pilocarpus microphyllus of the
Rutaceae family; some other alkaloids of this group have been isolated from this
plant, for example, isopilosine, epiisopilosine, and epiisopiloturine (Silva et al.
2013; Debnath etal. 2018).
5.2.2 Protoalkaloids (Non-heterocyclics)
Chemically, protoalkaloids contain the nitrogen atom outside the ring, which
remains as part of a side chain, not as part of the heterocyclic system; it can be
derived from amino acids or from biogenic amines. Some protoalkaloids are mes-
caline, ephedrine, colchicine, cathinone, etc.; however, they are not so common in
nature (Wansi etal. 2013; Talapatra and Talapatra 2015; Jayakumar and Murugan
2016; Kukula-Koch and Widelski 2017). Protoalkaloids can be derived from
L-tyrosine and L-tryptophan, which derive into phenylethylamine and terpenoid
indole, respectively (Alves de Almeida etal. 2017). Mescaline is one of the most
common phenylethylamine alkaloids and can be obtained from Lophophora wil-
liamsii, commonly known known as peyote (Beyer etal. 2009). On the other hand,
monoterpenoid indole alkaloids are a fairly large group in which around 3000 have
been identied in families as Apocynaceae, Loganiaceae, and Rubiaceae (Pan etal.
2016).
E. P. Gutiérrez-Grijalva et al.
95
5.2.3 Pseudoalkaloids
Pseudoalkaloids are heterocyclic containing nitrogen compounds but are not derived
from amino acids; they are generally derivatives of acetate, pyruvic acid, adenine/
guanine, or geraniol (Aniszewski 2015). As an example of this group, we can men-
tion the diterpenoid alkaloids (of 18, 19, and 20 carbons) obtained from a variety of
sources such as the genus Aconitum, Consolida, and Delphinium (Wang etal. 2010;
Gao etal. 2012).
5.3 Plant Sources ofAlkaloids
A plant is considered as a source of alkaloids when the species contain more than
0.001% of alkaloids (Wang and Liang 2009). In the present section of this chapter,
we present a summarized compilation of botanical families of plants which are
sources of alkaloids of pharmacological importance.
5.3.1 The Amaryllidaceae Family
Amaryllidaceae is a family of monocotyledonous plants with signicant economic
importance for its horticultural and ornamental appeal as well as its medicinal value.
The family Amaryllidaceae is composed of about 1100 species in 75 genera that are
distributed in warm tropical and subtropical zones around the world, including South
America, the Mediterranean, and Southern Africa (Nair etal. 2013). The leaves are
eshy and two-ranked with parallel veins with linear, strap-like, oblong, elliptic, lan-
ceolate, or liform shape. The owers are bisexuals and typically arranged in umbels,
and the fruit is dry and capsule shaped or eshy and berry-like. More than 100 alka-
loids have been isolated from Amaryllidaceae plants, andsome of them are shown in
Table5.2, which exert a wide range of interesting physiological effects.
Table 5.2 Plant alkaloids from the Amaryllidaceae family
Plant Common name Alkaloids References
Crinum
powelli
Cape lily Lycorine, 1-O-acetyl lycorine
Ismine
Nino etal. (2007)
Hippeastrum
puniceum
Easter lily Didehydroanhydrolycorine, lycorine,
narciclasine, pancratistain
Cortes etal. (2015)
Santana etal. (2008)
Lycoris
radiata
Hurricane lily Dehydrodihydrolycorine,
6β-acetoxycrinamine,
O-acetylhomolycorine, N-oxide,
caranine, ungerine, homolycorine
Feng etal. (2011)
Huang etal. (2013)
Hippeastrum
vittatum
Bulb mavem Montanine, lycorine, vittatine,
vittacarboline, ismine,
O-methylamine, pancracine,
hippadine
Silva etal. (2008)
Youssef (2001)
5 Plant Alkaloids: Structures andBioactive Properties
96
5.3.2 The Apocynaceae Family
Plants of the Apocynaceae family, commonly known as oleander or dogbane family,
are most commonly found in tropical and subtropical regions and have ornamental
value. These plants are well known for their alkaloid content. The Apocynaceae
family is composed of around 200 species and about 2000 genera of trees, shrubs,
herbs, and lianas or vines sometimes succulents or cactus-like. The herbs, shrubs,
and trees have opposite leaves and a milky, latex sap (Joselin etal. 2012). The ow-
ers are bisexual and regular, with ve united sepals, ve united petals, and ve sta-
mens; stamens attach at the base of the petals, alternate with the lobes. Some typical
genera of the Apocynaceae family includes Angadenia, Apocynum, Asclepias,
Catharanthus, Ceropegia, Cynanchum, Gonolobus, Hoya, Mandevilla, Morrenia,
Secamone, and Vallesia, many of which are poisonous; however, in correct dosage,
they are useful in current medicine (Table5.3).
Table 5.3 Plant alkaloids from the Apocynaceae family
Plant
Common
name Alkaloids References
Alstonia
angustiloba
Red-leafed
pulai
Yohimbine, cathafoline, cabucraline,
vincamajine, normacusine B,
lochnerine, alstophylline,
macralstonine, villalstonine,
alstilobanine
Ghedira etal.
(1998)
Ku etal.
(2011)
Alstonia scholaris White cheese
wood
Echitamine, tubotaiwine, akuammicine,
echitamidine, alstonamine, rhazmanine,
strictamine, manilamine, angustilobine,
vallesamine, tubotaiwine
Roy (2015)
Macabeo etal.
(2005)
Catharanthus
roseus
Madagascar
periwinkle
Catharanthine, vindoline, vincristine,
serpentine, vinblastine, ajmalicine
Hisiger and
Jolicoeur
(2007)
Cynanchum
paniculatum
Swallow-wort
root
Antone Lee etal.
(2003)
Holarrhena
oribunda
Kurchi bark Holarrhesine; holadiene; conessine Hoyer etal.
(1978)
Ochrosia elliptica Elliptic
yellow wood
Ellipticine; methoxy ellipticine;
elliptinine; isoreserpiline; cathenamime;
pleiocarpamine; apparicine; epchrosine;
tetrahydroalstonine
Chen etal.
(2017)
Plumeria alba Caterpillar
tree
Pagoda tree
Pigeonwood
Curine; evonine; voacamine;
tubocurarine chloride; syrosingopine
Sibi etal.
(2014)
Rauwola
vomitoria
Poison devil’s
pepper
Sarpagan; picrinine; akuammiline;
heteroyohimbine; yohimbine; aricine;
isoreserpiline; rauvoxine; rauvoxinine
Patel etal.
(1964)
Rauvola caffra Quinine tree Strictamine; sarpagan; akuammicine;
indolenine; corynane; peraksine;
yohimbine; suaveoline;
heteroyohimbine; oxindole
Milugo etal.
(2013)
Tabernaemontana
divaricata
Pinwheel
ower
Cononitarine B; conophylline Zalaludin
(2015)
E. P. Gutiérrez-Grijalva et al.
97
5.3.3 The Papaveraceae Family
Plants from the Papaveraceae family are dicotyledonous owering plants that pos-
sess leaves lobed or dissected, with bisexual owers in color red, white, violet, or
yellow and fruits in the form of capsules with dark seeds. Papaveraceae plants con-
tain about 42 genera which includes Canbya, Argemone, Corydalis, Romneya,
Arctomecon, Stylomecon, Mechonopsis, Hunnemannia, Dendromecon,
Eschscholzia, Meconella, Fumaria, Glaucium, Macleaya, Sanguinaria, and
Papaver, among others, with 775 species, distributed mainly in the subtropical and
temperate regions of northern hemisphere (Xu and Deng 2017). Papaveraceae plants
are strong narcotics, and also have biological and medical importance. Papaveraceae
plants contain L-tyrosine-derived alkaloids such as morphine, codeine, and noscap-
ine from Papaver somniferum and protopine, isocorydine, stylophye, rhoeadine,
coptisine, and tetrahydropalmatine from Papaver rhoeas. These have irreplaceable
therapeutic value in the treatment of many diseases. In addition, different alkaloids
belonging to this family have been reported (Table5.4).
5.3.4 The Asteraceae Family
The Asteraceae family is one of the largest families of owering plants, consisting
of approximately 1600 genera and over 23,000 species with a variety of morpho-
logical traits from trees of up to 30m tall and small herbs of approximately 1cm
height; owering heads occur in an amazing range of colors, sizes, and shapes
(Bohm and Stuessy 2001), unisexual or bisexuals, sometimes sterile calyx reduced,
corolla attened, or tubular, and leaves alternate, opposite, or whorled exstipulate.
Table 5.4 Important alkaloids from plants of Papaveraceae family
Plant
Common
name Alkaloids References
Tabernaemontana
divaricata
Pinwheel
ower
Voaphylline Zalaludin (2015)
Glaucium avum Yellow horned
poppy
Glaucine, talikmidine,
isocorydine, norisocorydine
Petitto etal.
(2010)
Glaucium
grandiorum
Red horned
poppy
Corydine, isocorydine,
oxoglaucine, pontevedrine
Kintsurashvili and
Vachnadze (2000)
Chelidonium majus
L.
Chelidonine, chelerythrine,
sanguinarine, isochelidonine
Ciric etal. (2008)
Argemone
mexicana
Flowering
thistle
13-Oxoprotopine, protomexicine,
dehydrocorydalmine,
jatrorrhizine
Singh etal. (2016)
Chelidonium majus Swallowwort Chelidonine, berberine, coptisine,
sanguinarine, chelerythrine
Gañán etal.
(2016)
Sanguinaria
canadensis
Bloodroot Sanguinarine, chelerythrine,
chelilutine, sanguirubine,
chelirubine, allocryptopine
Croaker etal.
(2016)
5 Plant Alkaloids: Structures andBioactive Properties
98
The most common genera are Ambrosia, Artemisia, Aster, Bidens, Centaurea,
Cirsium, Elephantopus, Gaillardia, Helianthus, Jurinea, Liatris, Rudbeckia,
Senecio, and Vermonia (Table5.5).
5.3.5 The Solanaceae Family
The Solanaceae family contains 90 genera and more than 2000 species distributed
in all continents and are abundant in alkaloids. Some typical genera are Brugmansia,
Atropa, Datura, Physalis, Mandragora, Solanum, Petunia, Nicotiana tabacum,
Physalis, and Lycium. Plants from the Solanaceae family can take the form of herbs,
shrubs, trees, and vines, and sometimes epiphytes, and can be annuals, biennials, or
perennials, and some have tubers. They do not produce latex or colorless saps. The
leaves are generally alternate or alternate at the base of the plant and opposed toward
the inorescence, and the leaves can be herbaceous, leathery, or transformed into
spines. The plant species belonging to this family grow especially in the tropic and
subtropics. The majority of the species occur in Central and South America.
Hyoscyamine, hyoscine, and cuscohygrine are tropan alkaloids from Atropa bella-
donna L. (Pérez-Amador etal. 2007). Some species with important alkaloid content
are listed in Table5.6.
5.3.6 The Rutaceae Family
The citrus botanical family (Rutaceae) is distributed across tropical and subtropical
areas. Some species such as Dictamnus albus, Skimmia japonica, and Acronychia
baueri contain the anthranilic acid-derived alkaloids such as dictamnine, skimmi-
anine, and acronycine, respectively. Alkaloids derived from L-histidine such as pilo-
carpine and pilosine are present in the species Pilocarpus microphyllus and P.
jaborandi (Santos, Moreno 2004). Non-citrus fruits with alkaloids include white
sapote, orangeberry, clymenia, and limeberry (Table5.7).
Table 5.5 Alkaloids of Asteraceae family
Plant Common name Alkaloids References
Ageratum
conyzoides
Billy goat weed
Chickweed
Lycopsamine, echinatine Wiedenfeld and
Roder (1991)
Centaurea
montana
Mountain bluet Montanoside Shoeb etal.
(2006)
Centaurea
schischkinii
Schischkiniin, montamine Shoeb etal.
(2005)
Senecio
cineraria
Silver dust Senecionine, seneciphylline,
integerrimine, jacobine, jacozine,
jacoline, jaconine, otosenine,
orosenine, oridanine, doronine
Tundis etal.
(2007)
E. P. Gutiérrez-Grijalva et al.
99
5.3.7 The Fabaceae Family
This plant family is the third largest botanical family and is rich with alkaloids
derived from L-ornithine and L-tryptophan such as eserine, eseramine, physove-
nine, and geneserine which can be found in Physostigma venenosum. Also alka-
loids from Fabaceae family are derived from L-tyrosine like jasmonoyl-S-dopa and
N-jasmonoyl isolated from Vicia faba; and alkaloids are derived from L-lysine like
lupinine, sparteine, lupanine, angustifoline, epilupinine, and anagyrine, among
others (Table5.8). Plants of the Fabaceae family grow in humid tropics, subtropics,
and temperate and subarctic regions around the globe, with 18,000 species and 650
genera, among them Acacia, Albizia, Baptisia, Cassia, Cercis, Dalea, Delonix,
Erythrina, Glycine, Mimosa, Parkia, Phaseolus, etc. (Kramell etal. 2005).
5.3.8 The Rubiaceae Family
The Rubiaceae family is characterized with owering plants known as bedstraw fam-
ily. They are terrestrial trees, shrubs, lianas, or herbs. It is the fourth largest angio-
sperm family that contains about 13,500 species in 611 genera, such as Acranthera,
Aidia, Aidiopsis, Airosperma, Alberta, Anthorrhiza, Appunia, Badusa, Benkara,
Bobea, Borojoa, Bouvardia, Breonadia, Capirona, Calycosia, Canthium, Ceriscoides,
Chassalia, Chione, Cigarilla, Coffea, Coptosapelta, Cowiea, Cuviera, Cubanola,
Danais, Dichilanthe, Deppea, Geophila, Gouldia, Greenea, Haldina, Hamelia,
Phitopis, Pinckneya, Pimentelia, Pomax, Praravina, Pseudopyxis, Ramosmania,
Rennellia, Rubia, Rustia, Sacosperma, Schachtia, Saldinia, Serissa, Simira,
Sinoadina, Sommera, Stevensia, Stipularia, and Suberanthus, among others. Most of
its species that are present in the subtropical regions belong to Cinchona (source of
quinine) and have high commercial values (Table5.9) (Nadkarni etal. 1995). Due to
Table 5.6 Alkaloids from plants of the Solanaceae family
Plant Common name Alkaloids References
Datura innoxia Downy thorn
apple
Acetylcopine, atropine,
scopolamine, hysoscyamine
El Bazaoui etal.
(2012)
Duboisia
myoporoides
Corkwood Scopolamine, hysoscyamine,
butropine, apoatropine
Palazón etal.
(2003)
Nicotiana
glauca
Tree tobacco Anabasine, nornicotine Mizrachi etal.
(2000)
Physalis minima Ground cherry Phygrine, withaminimim Basey etal. (1992)
Solanum
dulcamara
Bittersweet Solanine, solasodine, solamarine Kumar etal. (2009)
Solanum nigrum Black
nightshade
Solasodine Jiang etal. (2006)
Solanum torvum Turkeyberry Solasodine, solasonine,
solamargine
Pérez-Amador
etal. (2007)
5 Plant Alkaloids: Structures andBioactive Properties
100
Table 5.7 Alkaloids from Rutaceae family
Plant
Common
name Alkaloids Reference Alkaloids References
Aegle
marmelos
Bael tree Aegeline, marmeline, shahidine, skimmianine,
ethyl cinnamamide
Sugeng
etal.
(2001)
Yadav and
Chanotia
(2009)
Aegeline, marmeline, shahidine, skimmianine,
ethyl cinnamamide
Sugeng
Riyanto
etal.
(2001);
Yadav and
Chanotia
(2009)
Casimiroa
edulis
White
sapote
Edulein, scopoletin, zapoterin, casimiroedine Awaad
etal.
(2012)
Edulein, scopoletin, zapoterin, casimiroedine Awaad etal.
(2012)
Evodia
rutaecarpa
Wu Zhu
Yu or
Evodia
fruit
Evodiamine, rutaecarpine, evocarpine, 1-methy-
2-[(6Z,9Z)]-6,9-pentadecadienyl-4-(1H)-
quinolone (IV),
1-methyl-2-dodecyl-4-(1H)-quinolone (V)
Jiang and
Hu (2009)
Evodiamine, rutaecarpine, evocarpine, 1-methy-
2-[(6Z,9Z)]-6,9-pentadecadienyl-4-(1H)-
quinolone (IV),
1-methyl-2-dodecyl-4-(1H)-quinolone (V)
Jiang and
Hu (2009)
Skimmia
japonica
Japanese
skimmia
Skimmianine Sackett
etal.
(2007)
Skimmianine Sackett,
Towers, and
Isman
(2007)
Toddalia
asiatica
Orange
tree
8-Methoxynorchelerythrine,
11-demethylrhoifoline B, 8-methoxynitidine,
8-acetylnorchelerythrine,
8,9,10,12-tetramethoxynorchelerythrine,
isointegriamide, 1-demethyl dicentrinone,
11-hydroxy-10-methoxy-(2,3),methylenedioxytet
rahydroprotoberberine, nitidine, magnoorine,
8-methoxynitidine
Hu etal.
(2014)
8-Methoxynorchelerythrine,
11-demethylrhoifoline B, 8-methoxynitidine,
8-acetylnorchelerythrine,
8,9,10,12-tetramethoxynorchelerythrine,
isointegriamide, 1-demethyl dicentrinone,
11-hydroxy-10-methoxy-(2,3),methylenedioxytet
rahydroprotoberberine, nitidine, magnoorine,
8-methoxynitidine
Hu etal.
(2014)
E. P. Gutiérrez-Grijalva et al.
101
the increasing studies claiming potential human health promotion effects, alkaloids
have been gaining popularity around the world and are currently being used as major
therapeutic agents (Table5.10).
5.4 Bioactive Properties ofPlant Alkaloids
Plant alkaloids have been used as medicines, since ancient times, and their use is
widespread around the world. The ethnobotanical use of alkaloid-rich plants led the
way to elucidate, isolate, and evaluate the pharmacological properties of these com-
pounds that have ended in the production of several drugs, whichare beingused at
Table 5.8 Alkaloids from Fabaceae family
Plant
Common
name Alkaloids References
Albizia
gummifera
Peacock
ower
Budmunchiamine K
Budmunchiamine G
Normethylbudmunchiamine K
Rukunga and
Waterman
(1996)
Mahlangu
etal. (2017)
Erythrina
variegata
Tiger claw Spirocyclic (6/5/6/6) erythrivarine A (1),
spiro-fused (6/5/7/6) rings erythrivarine B
Suryawanshi
and Patel
(2011)
Zhang etal.
(2014)
Sophora
avescens
Shrubby
sophora
12α-Hydroxysophocarpine, oxymatrine,
matrine, 9α-hydroxymatrine, allomatrine,
oxysophocarpine, sophocarpine, anagyrine,
9α-hydroxysophocarpine, lehmannine,
13,14-dehydrosophoridine
Ding etal.
(2006)
Table 5.9 Important alkaloids from Rubiaceae family
Plant Common name Alkaloids References
Cinchona
ofcinalis
Cinchona bark Quinine, quinidine, cinchonine,
cinchonidine
Song (2009)
Mitragyna
speciosa
Tang Corynoxine, mitragynine,
speciogynine, paynantheine,
corynoxine B
Poklis and Peace (2017)
Nauclea
orientalis
Bur tree Nauclecine; naucleactonine;
naucleaorals
Sichaem etal. (2012)
Zhang etal. (2001)
Psychotria
colorata
Calycanthine, isocalycanthine,
chimonanthine, hodgkinsine,
quadrigemine C
Verotta etal. (1998)
Uncaria
tomentosa
Cat’s claw Pteridine, speciophylline,
isomitraphylline, uncarine F,
mitraphylline, isopteropodine
Sandoval etal. (2002)
5 Plant Alkaloids: Structures andBioactive Properties
102
present. Alkaloids have been described with many uses; nowadays they are used as
chemotherapy agents, and alsoare being studied for their antidiabetic and neuropro-
tective capacity.
5.4.1 Anticancer Properties ofPlant Alkaloids
One of the main challenges in cancer treatment is the development of multidrug
resistance to chemotherapy agents, which is caused mainly by the efux of the
drugs by the p-glycoprotein (Joshi etal. 2017). Plant alkaloids are of interest in
plant medicinal chemistry and medicine due to their ability to act as anticancer
agents in some drug resistant-cancer types. Alkaloids also have been suggested for
the prevention and/or management of oxidative stress and inammation, both
related to cancer (Alasvand etal. 2019). Vinca alkaloids, such as vinblastine, vin-
cristine, vindesine, and vinorelbine, have shown antitumor activity against breast
cancer cells like MCF-7 and MDA-MB-231, hepatic cancer cells (HepG2, HepG2/
ADM), and leukemia cell line (K562). Their antitumor effect is hypothesized
through the electron-withdraw substituents on the ring, which may be associated
with their potential tubulin-binding activity (Zheng etal. 2013). Drug resistance is
a common problem during chemotherapy treatment, and some cell lines resistant to
some chemotherapeutic agents have shown sensibility to treatment with alkaloids
such MCF-7TXT, a docetaxel-resistant cell line, with the alkaloid colchicine in a
study by Wang etal. (2017). The authors also reported that the cell line MCF-7TXT
showed higher cytotoxicity against the alkaloids vinorelbine and vinblastine than
the non-resistant MCF-7 cc cell line. Moreover, the authors showed that the
docetaxel-resistant MCF-7 cells were cross-resistant to vinca alkaloids, but sensi-
tive to colchicine, 2MeOE2, ABT-751, and CA-4P, which are microtubule-targeting
Table 5.10 Anticancer properties of plant alkaloids
Alkaloid type Alkaloids Anticancer effect References
Vinca
alkaloids
Vinblastine,
vincristine, vindesine,
and vinorelbine
Antitumor activity against MCF-7,
MDA-MB-231, HepG2, HepG2/
ADM, and K562 cells
Zheng etal.
(2013)
Mitragyna
speciosa
Tang Corynoxine, mitragynine,
speciogynine, paynantheine,
corynoxine B
Poklis and
Peace (2017)
Nauclea
orientalis
Bur tree Nauclecine; naucleactonine;
naucleaorals
Sichaem etal.
(2012)
Zhang etal.
(2001)
Psychotria
colorata
Calycanthine, isocalycanthine,
chimonanthine, hodgkinsine,
quadrigemine C
Verotta etal.
(1998)
Uncaria
tomentosa
Cat’s claw Pteridine, speciophylline,
isomitraphylline, uncarine F,
mitraphylline, isopteropodine
Sandoval etal.
(2002)
E. P. Gutiérrez-Grijalva et al.
103
agents, that are considered as one of the most reliable classes of anti-neoplastic
drugs in the treatment of breast cancer. As aforementioned, drug resistance is a per-
sistent problem during chemotherapy treatment in cancer patients. For example,
during pemetrexed therapy, the enzyme thymidylate synthase levels are enhanced in
cancer tissue of nonsquamous non-small cell lung cancer. Chiu etal. (2017) reported
that vinca alkaloids in invivo studies with vinblastine and invitro studies with vin-
cristine can successfully inhibit the growth of pemetrexed-resistant tumors. Vinca
alkaloids regulate the ERK-mediated pathway, which is a regulator of apoptosis
induced by pemetrexed. Moreover, one of the most common and important classes
of anticancer agents are tubulin-binding compounds, which interfere with microtu-
bule assembly leading to mitotic arrest. However, most of these compounds are
cytotoxic; thus new compounds from natural origin are being studied. For instance,
vinblastine, vincristine, vindesine, and vinorelbine are known antimitotic drugs, and
Zheng etal. (2013) showed that the structural differences among these compounds
affect their antitumor properties and their toxicity. The authors reported that these
alkaloids showed moderate antitumor activity in MCF-7, MDA-MB-231, HepG2,
HepG2/ADM, and K562 cell lines; and this effect is suggested to be mediated by
electron-withdraw substituents from the ring structure. Another molecular mecha-
nism related to tumor cell growth is the interaction between high-mobility group
box 1 protein and receptor for advanced glycation end products. The high-mobility
group box 1 protein is a nonhistone DNA-binding protein involved in inammation,
cell migration, cell death, and tumor metastasis with high afnity to receptors for
advanced glycation end products, which are related to inammation, tumor cell
growth, migration, and invasion (Sims etal. 2010). In this sense, Inada etal. (2019)
evaluated the potential of the alkaloid papaverine as anticancer agent in human glio-
blastoma (GGB) temozolomide-sensitive U87MG and TMZ-resistant T98G cells
and reported that, in fact, papaverine can prevent tumor growth promotion by inhi-
bition of the high-mobility group box 1 protein in human glioblastoma temozolomide-
sensitive U87MG and TMZ-resistant T98G cells. Additionally, a study by Xie etal.
(2019) with amide alkaloids from Piper nigrum showed that dimeric alkaloids such
as pipernigramide A; pipernigramide B, an unknown new identied natural com-
pound; chabamide; chabamide I; nigramide B; and piperine enhanced the sensibili-
zation of paclitaxel-resistant cervical cancer cells HeLa/PTX. These alkaloids
signicantly enhanced the anticancer apoptotic effect of paclitaxel. Furthermore,
the combination treatment of P. nigrum alkaloids at 50μM and paclitaxel enhanced
the apoptotic effect through increased cleavage of PARP and caspase-3. The alka-
loid piperine enhanced the response of paclitaxel-resistant cervical cancer cells; this
effect was mediated by a change in the expression of molecules related with the
apoptotic pathway. Furthermore, combination treatment decreased the protein
expression of phosphor-Akt and Mcl-1, which are involved in the paclitaxel resis-
tance process in cancer cells. It has been reported that the antioxidative transcription
nuclear factor Nrf2 increases during tumor malignancy in cancer cells such as
colonic, thyroid, endometrial, lung, breast, and pancreatic cancer cells. This may
cause alterations that may affect the genetic material, such as loss-of-function muta-
tions and promotion of hypermethylation, and also chemoresistance. Since some
5 Plant Alkaloids: Structures andBioactive Properties
104
alkaloids have shown potential to be Nrf2 inhibitors, Arlt etal. (2013) evaluated the
suppressive effect of trigonelline on Nrf2 activity in pancreatic cancer cells. The
authors showed that trigonelline exerted high inhibitory effect on Nrf2 activity at
doses from 0.1 to 1μM; interestingly higher doses were less efcient/ineffective.
The alkaloid trigonelline decreased the nuclear level of Nrf2 protein but not its
overall expression (Arlt et al. 2013). Amusingly, no adverse effects have been
reported for trigonelline in human studies.
Alkaloids are currently promising compounds to be used in cancer treatment,
alone or in combination with other anticancer therapies. However, further studies
are still necessary to fully understand their molecular and cellular mechanism of
action as well as their toxicity and pharmacological properties.
5.4.2 Antidiabetic Properties ofPlant Alkaloids
Several reports have shown promising studies on the antidiabetic properties of alka-
loids from different plants, such as Rhizoma coptidis, Trigonella foenum-graecum,
Berberis vulgaris, and Ervatamia microphylla, which have been reported to exert
their antidiabetic potential through several mechanisms such as diminishing insulin
resistance, promoting insulin secretion, and ameliorating gut microbiota structures,
among others (Zhou etal. 2012; Pirillo and Catapano 2015; Mirhadi etal. 2018;
Umezawa etal. 2018; Ma etal. 2019).
For instance, Coptis chinensis alkaloids like berberine, epiberberine, coptisine,
palmitine, and magnoorine have been related with anti-obesity effects. Choi etal.
(2014) showed that C. chinensis alkaloids inhibit adipogenesis in 3T3-L1 cells;
alkaloid action was dose dependent without any apparent cytotoxic effect. The
authors suggest that the potential obesity-ameliorating effect of Coptis alkaloids is
through the downregulation of major adipogenic transcription activators such as
PPAR-γ and C/EBP-α proteins. Further, in vivo research and clinical trials are
needed to clarify the efcacy, safety, and precise molecular mechanisms of the anti-
obesity effects of these alkaloids.
Plant alkaloids can also be potential antidiabetic agents by their potent α-glucosidase
inhibitory activity. Choudhary etal. (2011) showed that nummularine- R, nummularin-
C, and hemsine-A cyclopeptide alkaloids isolated from Ziziphus oxyphylla Edgw are
potent α-glucosidase inhibitor with IC50 values of 212.1, 215.1, and 394.0μM, respec-
tively and that the alkaloids nummularine-R and hemsine-A are also anti-glycation
agents. Moreover, Choi etal. (2015) reported that alkaloids from rhizome of Coptis
chinensis, identied as berberine, epiberberine, magnoorine, and coptisine, possess
antidiabetic effect mediated by their inhibitory potential against protein tyrosine phos-
phatase 1B, a non-transmembrane protein tyrosine phosphatase, an enzyme in which
its overproduction is involved in the onset of non-insulin-dependent diabetes mellitus.
The authors reported that the evaluated alkaloids had inhibitory activities against
PTP1B with IC50 vales of 16.3, 24.19, 28.14, and 51.04μM, respectively, and that this
inhibition was mixed-type for berberine and epiberberine and noncompetitive for mag-
noorine and coptisine. Furthermore, a docking simulation analysis showed that the
E. P. Gutiérrez-Grijalva et al.
105
evaluated alkaloids have high proximity to PTP1B residues, including Phe182 and
Asp181in the WPD loop, Cys215in the active sites, and Tyr46, Arg47, Asp48, Val49,
Ser216, Ala217, Gly218, Ile219, Gly220, Arg221, and Gln262in the pocket site, which
indicates a higher afnity and tighter binding capacity of these alkaloids for the active
site of the enzyme. Another study by Hulcova etal. (2018) showed that Amaryllidaceae
alkaloids are potential glycogen synthase kinase 3β inhibitors. Twenty-eight alkaloids
of seven structural types (1) belladine, (2–6) haemanthamine, (7–10) crinine, (11–13)
galanthamine, (14–19) lycorine, (20) tazettine, and (21–28) homoycorine were reported
by the authors. Only caranine, 9-O-demethylhomolycorine, and masonine showed gly-
cogen synthase kinase 3β inhibitory activity above 50%. Interestingly, the two homoly-
corine-type Amaryllidaceae alkaloids, masonine and 9-O-demethylhomolycorine, and
one lycorine-type alkaloid caranine showed the highest IC50 values with 27.81, 30, and
30.75μM, respectively. Interestingly, the authors described a detailed structure-activity
relationship where the presence of hydroxyl substitution at position 2, as in hip-
peastrine, is connected with a distinct reduction of GSK-3β inhibitory activity com-
pared with masonine, 9-O-demethylhomolycorine, oduline, and O-ethyllycorenine,
where no substituent in position C-2 is present. The opening of the tetrahydropyrane
ring in tetrahydromasonine also reduces the GSK-3β inhibitory potency of homolyco-
rine-type alkaloids. However, further structure-activity relationship studies are needed.
Moreover, Ullah etal. (2018) reported that streptozotocin-induced diabetic rats treated
with steroidal alkaloids from Sarcococca saligna at a subcutaneous dose of 5mg/kg
reduced the glucose level in blood. This effect was attributed to the alkaloids sarcovag-
ine- D and holaphylline, and also these alkaloids were related with the good improve-
ment in blood lipids. It is important to mention that abnormal lipid levels in diabetic
patients may produce hypertriglyceridemia and high cholesterol in blood. A 4-week
study by Zhang etal. (2018) showed that alkaloids from Litsea glutinosa barks in ob/
ob mice at doses of 50, 100, and 200mg/kg decreased body and fat weights without
reducing average food intake in treated mice; the efciency of the treatment was simi-
lar to that of metformin. The identied alkaloids in the extracts used in the treatment
were laurelliptine, 6-isoquinolinol, laurolitsine, isoboldine, N-methyl laurolitsine, lau-
rolitsine, boldine, and litseglutine. Furthermore, the L. glutinosa alkaloid extracts at
concentrations ranging from 100 to 200mg/kg signicantly reduced the serum levels
of fasting glucose, glycosylated hemoglobin, and glycosylated serum protein. The
authors also showed that the alkaloid extract from L. glutinosa signicantly enhanced
the activity of liver glucokinase, a key enzyme in glycogen synthesis, and increased the
content of hepatic glycogen. Moreover, a chronic inammation is a common character-
istic of diabetes, which may lead to insulin resistance; in this regard, the alkaloid treat-
ment signicantly decreased the inammation markers such as MCP-1, TNF-α, and
IL-6. The vindoline, vindolidine, vindolicine, and vindolinine, alkaloids from the
dichloromethane extract of C. roseus, induced high glucose uptake in pancreatic β-T6
cells at a concentration of 25μg/ml. Furthermore, the alkaloids vindolidine, vindoli-
cine, and vindolinine demonstrated inhibitory activity against tyrosine phosphatase
1B. Also, C. roseus alkaloids showed a higher antioxidant activity than quercetin,
which may be involved in controlling oxidative stress damage caused by ROS produc-
tion, and is related with the onset of diabetes comorbidities such as cardiovascular
5 Plant Alkaloids: Structures andBioactive Properties
106
problems like atherosclerosis (Tiong et al. 2013; Halliwell and Gutteridge 2015).
Alkaloids also have the potential to be antidiabetic agents due to their modulation of
blood glucose and lipid content. For example, Capparis decidua alkaloids attenuated
the activity of glucose 6-phosphatase by 44% in streptozotocin-induced diabetic mice.
Moreover, liver and muscle glycogen content also improved by 33 and 28%, respec-
tively, with alkaloid treatment. In this regard, the lipid prole of alkaloid-treated mice
as well as their level of total cholesterol, low-density lipoprotein, and triglyceride
decreased around 25, 32, and 27%, respectively. On the other hand, the level of high-
density lipoprotein improved by 28% with alkaloid treatment (Sharma etal. 2010). The
authors also evaluated the mechanism of action by evaluating the expression proles of
genes involved in glucose homeostasis from alkaloid-treated mice. Expression of glu-
cose regulatory genes, G6Pase and PEPCK, reduced clearly in the treated group. On
the other hand, hepatic GK and Glut-4 expression improved signicantly in compari-
son to the diabetic untreated group. Also, streptozotocin-induced upregulation of
TNF-α in adipose tissue was signicantly downregulated by the alkaloid treatment.
Moreover, transcription of PPAR-α gene also increased in the adipocytes of the treated
diabetic mice; there was almost no change in the level of PPAR-α. Interestingly, alka-
loids managed to reduce renal aldose reductase expression in treated animals as com-
pared to untreated mice.
5.4.3 Plant Alkaloids andAlzheimer’s Disease
Several plant alkaloids are of interest due to their potential to be used as drugs to
treat neurodegenerative disorders such as Huntington disease, Parkinson’s disease,
epilepsy, schizophrenia, and Alzheimer’s disease (Hussain etal. 2018). Alzheimer’s
disease is one of the major neurodegenerative diseases and is characterized by pro-
gressive deterioration of memory, learning, and other cognitive functions. The main
hallmarks of Alzheimer’s disease are the accumulation of amyloid plaques contain-
ing extracellular deposits of β-amyloid peptide and intraneuronal neurobrillary
tangles, which lead to neuronal cell loss in the nucleus basalis of Meynert and in the
hippocampus (Konrath etal. 2013; Hussain etal. 2018). Furthermore, normal cells
have a neuronal microtubule-associated protein called tau protein to stabilize the
axonal microtubules;however, in Alzheimer’s disease, this protein becomes hyper-
phosphorylated by kinases disassociating it, thus destabilizing the microtubule net-
work, cytoskeletal collapse, loss of viability and neuronal cell death. Interestingly,
the β-amyloid peptide accelerates tau protein aggregation, and reduction of the
β-amyloid peptide expression may block the amyloid-induced neuronal dysfunction
(Ng etal. 2015). In this regard, alkaloids may have a role in Alzheimer’s disease,
since they have the potential to be good inhibitors of acetylcholinesterase, a key
enzyme in the breakdown of acetylcholine, involved in Alzheimer’s disease (Konrath
etal. 2013).
As it has been established, the chemical structure of compounds with bioactive
properties on health promotion inuences heavily on their activity. In this regard, a
study by McNulty etal. (2010) showed that the inhibition of alkaloid-1- acetyllycorine,
E. P. Gutiérrez-Grijalva et al.
107
a potent Amaryllidaceae alkaloid with acetylcholinesterase inhibition capacity, func-
tions through their ability to act as hydrogen bond acceptor, analogous to the –OH
group of galanthamine, and also the introduction of lipophilic substituents at C-1 and
C-2 plays a pivotal role on their acetylcholinesterase inhibitory potential. Also, the
distribution of alkaloids in each plant source heavily inuences their potential bioac-
tive effect, which may be the result of a synergistic effect or by a single compound.
On this subject, Cardoso-Lopes etal. (2010) reported that the solvent of choice to
extract alkaloids from plants has a signicant effect on their inhibitory rate on the
acetylcholinesterase enzyme, which, as aforementioned, may be related to the alka-
loid composition in each solvent fraction. The authors used ethanol, hexane, and
alkaloid fractions of Esenbeckia leiocarpa, which showed acetylcholinesterase
inhibitory rates with IC50 values of 50.7, 6.0, and 1.6μg/mL, respectively. This inhib-
itory activity was related with the presence of alkaloids such as leiokinine A, lep-
tomerine, kokusaginine, skimmianine, masculine, and indersiamine. Furthermore,
Zhan etal. (2010) isolated indole alkaloids from Ervatamia hainanensis to identify
the compound responsible for the acetylcholinesterase inhibitory activity. They
reported that the alkaloids coronaridine and voacangine have the same level of ace-
tylcholinesterase inhibitory potency as galantamine, a known inhibitor, with IC50 val-
ues of 8.6 and 4.4μM for coronaridine and voacangine, respectively. Interestingly,
voacangine is an analog of coronaridine, with a methoxyl at phenyl group displayed
nearly twofold improvement in acetylcholinesterase potency compared to coronari-
dine. Neuroinammation is a pathological hallmark of Alzheimer’s disease. In this
sense, microglial cells (specialized macrophages found in the nervous central sys-
tem) are activated by amyloid β peptide to produce increased amounts of proinam-
matory molecules such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6,
nitric oxide (NO), and reactive oxygen species. Furthermore, Ligusticum chuanxiong
is ethnobotanically used in oriental medicine to treat cardiovascular and cerebrovas-
cular diseases, and some studies have shown antioxidant and anti-inammatory
effects, and these properties have been linked to the alkaloid tetramethylpyrazine. On
this subject, the alkaloids tetramethylpyrazine have been able to suppress the activity
of Aβ1–42-induced proinammatory mediators and neurotoxicity; thus tetramethyl-
pyrazine is a potential alkaloid that can be used as treatment for neurodegenerative
diseases like Alzheimer’s disease (Kim et al. 2014). An in vivo study by
Chonpathompikunlert etal. (2010) reported that the oral administration of piperine
at doses from 5 to 20mg/kg BW during 2weeks to Wistar rats, showed that piperine,
at all doses, had a neuroprotective effect by measuring mice neuron density in regions
of the hippocampus, which resulted in improved memory impairment, decreased
escape latency, and increased retention time. However, due to the potential cytotoxic-
ity of piperine, further pre-clinical studies are needed before piperine is used in
humans.
Conversely, the use of alkaloids must be cautionary, since they may show toxic-
ity, and toxicity and pre-clinical studies are needed before they are used in humans.
For instance, it has been reported that Areca nut has been associated with oral and
pharyngeal cancers, which is associated with its arecoline content, an alkaloid that
has shown to be genotoxic and cytotoxic (Shih etal. 2010). Thus, Shih etal. (2010)
5 Plant Alkaloids: Structures andBioactive Properties
108
evaluated the mechanism of action of the cytotoxic effect of arecoline in rat primary
cortical neurons. They showed that arecoline at concentrations ranging from 50 to
200μM induced neuronal cell death and increased the production of reactive oxy-
gen species and mRNA levels of NADPH oxidase 2, and also arecoline enhanced
the expression of proapoptotic proteins, such as cytochrome C, Bax, caspase-9, and
caspase-3. Moreover, the authors also reported that antioxidant enzymes can attenu-
ate the redox disruption caused by arecoline.
5.5 Conclusion andFuture Perspectives
Alkaloids are a widespread group of compounds with extended use as medicinal
agents throughout the world, since ancient times. The chemical structural diversity,
distribution, and functional properties of alkaloids are very complex, as well as their
study. However, the importance of alkaloids as potential biopharmaceuticals relies
on the fact that nowadays, they are used as chemotherapeutic agents to treat dis-
eases, including cancer, diabetes, and neurological disorders. The search for new
alkaloids to treat chemotherapy-resistant cancers still continues. However, due to
the wide chemo-diversity of alkaloids, the work to describe their structures and
pharmacological properties are still needed alongside pre-clinical and clinical stud-
ies to test their safe use in humans.
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