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 CONTRIBUTORS

Numbers in parentheses indicate the pages on which the authors’ contributions begin.
Stefan Biastoff (49), Institute of Pharmacy, Martin Luther University Halle-Wit-
tenberg, 06120 Halle/Saale, Germany
Maria Fátima das Grac- as Fernandes da Silva (139), Departamento de Quı́mica,
Universidade Federal de São Carlos, 13565-905 São Carlos, SP, Brazil
Birgit Dräger (49), Institute of Pharmacy, Martin Luther University Halle-
Wittenberg, 06120 Halle/Saale, Germany
João Batista Fernandes (139), Departamento de Quı́mica, Universidade Federal
de São Carlos, 13565-905 São Carlos, SP, Brazil
Takashi Ohshima (103), Department of Chemistry, Graduate School of Engi-
neering Science, Osaka University, Osaka 560-8531, Japan
Masakatsu Shibasaki (103), Graduate School of Pharmaceutical Sciences, The
University of Tokyo, Tokyo 113-0033, Japan
Márcio Santos Soares (139), Departamento de Quı́mica, Universidade Federal de
São Carlos, 13565-905 São Carlos, SP, Brazil
Paulo Cezar Vieria (139), Departamento de Quı́mica, Universidade Federal de
São Carlos, 13565-905 São Carlos, SP, Brazil
Michael Wink (1), Institute of Pharmacy and Molecular Biotechnology, Univer-
sity of Heidelberg, 69120 Heidelberg, Germany

vii
 PREFACE

Once again, this volume of ‘‘The Alkaloids: Chemistry and Biology’’ is comprised of
four quite different chapters, from three different continents, on mechanisms of
cytotoxic action, the calystegines, strychnine synthesis, and substituted quinoline
alkaloids. This diversity reflects the need to see alkaloids as a class of natural
product having tremendous biological potential and of continued broad scientific
interest.
Numerous alkaloids have over the past 35 years shown cytotoxic activity. For
the first time, Wink, in Chapter 1, discusses the diverse mechanisms through
which various alkaloid classes, and individual compounds within those classes,
effect their activity. It is also made apparent that alkaloids offer opportunities to
overcome drug resistance, which is the nemesis of many therapeutic regimens
and requires more detailed studies.
While the tropane alkaloids are best known for pharmaceutical agents such as
cocaine and atropine, the development of the polyhydroxy tropane alkaloids, the
calystegines, has brought new challenges. In Chapter 2, the advances in the
isolation, structure determination, synthesis, biosynthetic pathways, and biology
of this relatively new group of alkaloids are discussed by Biastoff and Dräger.
Small molecules with a high number of stereocenters offer challenges to
synthetic organic chemists which are almost irresistable, and thus become model
systems for the evolution of new methodologies. In Chapter 3, one of these
archetypical alkaloids, strychnine, is reviewed solely from the perspective of
recent synthetic efforts by Shibasaki and Ohshima.
Finally, in Chapter 4, a new group of alkaloids, those with a quinoline nucleus
and various alkyl, aryl, and alkylaryl side chains, are discussed by the Brazilian
group of da Silva, Soares, Fernandes, and Vieria from the perspectives of
biosynthesis, biogenesis, and distribution in the plant, marine, and fungal
environments.

Geoffrey A. Cordell
University of Illinois at Chicago

ix
 CHAPT ER 1
Molecular Modes of Action of
Cytotoxic Alkaloids: From DNA
Intercalation, Spindle Poisoning,
Topoisomerase Inhibition to
Apoptosis and Multiple Drug
Resistance
Michael Wink

Contents I.Introduction 1
II.Molecular Targets of Secondary Metabolites 2
III.Cytotoxicity of Alkaloids 5
IV. Molecular Modes of Action of Cytotoxic Alkaloids 8
A. Interactions with DNA, RNA, and Associated Enzymes 8
B. Interactions with the Cytoskeleton 17
C. Induction of Apoptosis 20
D. Interactions with ABC Transporters and Cytochrome p450 22
V. Conclusions 37
Acknowledgments 38
References 38

I. INTRODUCTION

Plants produce a high diversity of secondary metabolites (SM), and among them,
alkaloids are a most prominent class. Over 21,000 alkaloids have been identified,

Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, 69120 Heidelberg, Germany
 Corresponding author.
E-mail address: [email protected] (M. Wink).
The Alkaloids, Volume 64 r 2007 Elsevier Inc.
ISSN 1099-4831, DOI 10.1016/S1099-4831(07)64001-2 All rights reserved

1
2 Michael Wink

which constitute the largest group among the nitrogen-containing SM (including

700 non-protein amino acids, 100 amines, 60 cyanogenic glycosides, 100 gluco-
sinolates, and 150 alkylamides). However, the class of SM without nitrogen is
even larger (more than 25,000 terpenoids, 7000 phenolics and polyphenols, 1000
polyacetylenes, fatty acids, waxes, and 200 carbohydrates) (1–4). Alkaloids are
widely distributed in the plant kingdom, especially among angiosperms (more
than 20% of all species produce alkaloids), and are less common in gymno-
sperms, lycopods, horsetails, mosses, and algae (3,5,6). Alkaloids also occur in
bacteria, fungi, many marine animals (sponges, slugs), arthropods, amphibians,
birds, and mammals (3,7–9).
Alkaloids are apparently important for the fitness of the organism that
produces them. One of the main functions is that of chemical defence against
herbivores or predators. Some alkaloids have antibacterial, antifungal, and
antiviral activities in addition. In many cases, a single alkaloid can exhibit more
than one biological function. During evolution, the constitution of alkaloids has
been modulated so that they usually contain more than one active functional
group allowing them to interact with several molecular targets. Therefore, a
pleiotropic effect is a common theme in alkaloids and other SM (2,3,7,8,10–13).
The multiple functions that alkaloids can exhibit include a few physiological
tasks: sometimes, toxic alkaloids also concomitantly serve as nitrogen-storage
and nitrogen-transport molecules. The ecological functions will not be reviewed
in this chapter as they were discussed in previous reviews (2,7,8,10,11).

II. MOLECULAR TARGETS OF SECONDARY METABOLITES

In order to deter, repel, or inhibit the diverse range of potential enemies, ranging
from arthropods, and vertebrates to bacteria, fungi, and viruses, alkaloids must
be able to interfere with important cellular and molecular targets. A short over-
view of these potential targets is given in Figures 1 and 2. The modulation of a
molecular target will negatively influence its communication with other compo-
nents of the cellular network, especially proteins (cross-talk of proteins), or
elements, or signal transducers. As a consequence, the metabolism and function
of cells, tissues, organs, and eventually the whole organism will be affected.
Although we know the structures of many SM, our knowledge concerning their
molecular mode(s) of action is largely fragmentary and incomplete. Such
knowledge is, however, important in order to understand the functions of SM
for the producing organism, and for the rational utilization of SM in medicine or
plant protection. Whereas many SM interact with multiple targets and thus have
unspecific broad activities, others are highly specific, and interact exclusively
with a particular target. SM with broad activities interact mainly with proteins,
biomembranes, and DNA/RNA (Table I).
Among broadly active alkaloids, a distinction can be made between those that
are able to form covalent bonds with proteins and nucleic acids, and those which
modulate the conformation of proteins and nucleic acids by non-covalent bond-
ing. Covalent bonds can be formed with reactive functional groups of SM, such as
 Molecular Modes of Action of Cytotoxic Alkaloids 3

Ribosomes DNA
•Tetracyclin DNA-polymerase
RNApolymerase
•Streptomycin Repair enzymes
•Erythromycin Topoisomerase
•Chloramphenicol •Intercalators
•Alkylants
•Protein inhibitors

Proteins
Enzymes
Structural proteins
Regulatory proteins
•Covalent modifications
•Non-covalent interactions
•Ligands
•Substrates;inhibitors

polysomes
plasmid
Biomembrane Cell wall
•Polymixins •Vancomycin
•Terpenoids •Penicillin
•Saponins •Cephalosporin

Figure 1 Molecular targets in bacteria that can be affected by natural products.

aldehydes, epoxides, SH groups, phenolic radicals, activated double bonds, and

exocyclic or terminal methylene groups (Table I) (4,13,14).
Non-covalent bonds, especially hydrogen bonds, ionic bonds, hydrophobic
interactions, and van der Waals forces are weak individually, but can be powerful
if they work co-operatively together. For example, a tannin typically has several
(more than 10) phenolic hydroxyl groups that can form hydrogen bonds with
proteins and nucleic acids. Furthermore, these OH groups may dissociate under
physiological conditions to form phenolate ions that can form ionic bonds with
positively charged amino acid residues, such as those from lysine, arginine, and
histidine. Phenolic hydroxyl groups are a common theme in many SM, mostly in
phenylpropanoids, flavonoids, tannins, and polyketides, and they also occur in
some alkaloids (especially in the isoquinoline and quinoline alkaloids). These OH
groups are crucial for the biological activity of phenolics.
Nitrogen-containing compounds, such as alkaloids, amines, and peptides
usually have positively charged N-atoms (under physiological conditions) in
their molecules that can form ionic bonds with negatively charged amino
acid residues of glutamic and aspartic acid in proteins. Both the covalent and
non-covalent interactions will modulate the three-dimensional protein structure,
i.e., the conformation that is so important for their bioactivities. A conformational
change is usually associated with a loss or reduction in the activity of a protein,
4 Michael Wink

•PROTEINS
Ion channels
Enzymes

Structural proteins

Regulatory proteins
Receptors Transporters •Covalent modifications
Signal
•Non-covalent interactions
transduction •Ligands
Y Y
•Substrates; inhibitors

Ribosomes
•Protein biosynthesis inhibitors
Microtubules
• Taxol
Biomembrane
• Colchicine
•Saponins
• Vinblastine
•Terpenoids
• Podophyllotoxin

Actin filaments
•Amphotericin B DNA
•Phalloidin
RNA polymerase

Repair enzymes

Topoisomerase I/II
ER &Golgi
DNA-polymerase
•Intercalators
•Alkylants
•Protein inhibitors

Mitochondria
•Respiratory chain
•ATP generation

Figure 2 Molecular targets in animal and human cells that can be affected by natural
products.

inhibiting enzyme, or receptor activity, or interference with the very important

protein–protein interactions (4,13,14).
Lipophilic compounds, such as the various terpenoids, tend to associate with
other hydrophobic molecules in a cell; these can be biomembranes or the
hydrophobic core of many proteins and of the DNA double helix (4,13,14). In
proteins, such hydrophobic and van der Waals interactions can also lead to con-
formational changes, and thus protein inactivation. A major target for terpenoids,
especially saponins, is the biomembrane. Saponins can also change the fluidity of
biomembranes, thus reducing their function as a permeation barrier. Saponins
can even make cells prone to leak, which immediately leads to cell death. This
can easily be seen in erythrocytes; when they are attacked by saponins these cells
burst and release hemoglobin (hemolysis) (4,13,14).
These pleiotropic, multitarget bioactivities are not specific, but are neverthe-
less effective, and this is what is critical in an ecological context. Compounds
with pleiotropic properties have the advantage that they can attack any enemy
that is encountered by a plant, be it a herbivore, a bacterium, fungus, or virus.
These classes of compounds are seldom unique constituents; quite often plants
produce a mixture of SM, often both phenolics and terpenoids, and thus exhibit
both covalent and non-covalent interactions. These activities are probably both
additive, and synergistic (13,14).
 Molecular Modes of Action of Cytotoxic Alkaloids 5

Table I Interactions of secondary metabolites with proteins and biomembranes

Mode of action Class of secondary metabolite

Covalent modifications
Reaction of aldehyde groups with Iridoids, terpenoids with aldehyde
amino groups groups
Reaction of isothiocyanate groups Mustard oils, (isothiocyanates)
with amino and SH groups
Reaction of a,b-unsaturated carbonyl Sesquiterpene lactones,
groups with SH groups phenylpropanoids, monoterpenes
Reaction of allylsulfides with SH Allicin
groups
Reaction of epoxides with proteins Valepotriates, metabolically activated
and DNA metabolites
Reaction with metal ions Quinones, naphthoquinones
Non-covalent bonds
Ionic bonds Phenolics, tannins, bases, acids
Hydrogen bonds Phenolics, tannins, anthraquinones
Van der Waals and hydrophobic Lipophilic compounds, such as
interactions terpenoids
Disturbance of membrane fluidity
Hydrophobic/amphiphilic Saponins and other terpenoids
interactions

Pharmacologists clearly prefer SM that interact with a single target in a

specific way (monotarget substances) because dose response and structure
activity relationships can be much more easily determined than for non-specific,
multitarget compounds. Many alkaloids fall in the class of specific modulators,
and have been modified during evolution in such a way that they mimic
endogenous ligands, hormones, or substrates. We have termed this selection
process ‘‘evolutionary molecular modeling’’ (7,8,11,12). Many alkaloids are
neurotoxins that were selected for defence against animals. These compounds
have the advantage for the plants producing them that they are usually not toxic
for the producing organism (as plants have no nerves). On the other hand, plants
need special capacities to produce and store the non-specific multitarget SM (7).
Table II lists the potential neuronal targets that can be affected by alkaloids.
Extensive reviews on this topic have been published (8,10,11). Since neuronal
signal transduction is a very critical target in animals, and its modulation usually
leads to toxic effects, many alkaloids are indeed strong (even deadly) poisons, or
have mind-altering and hallucinogenic properties.

III. CYTOTOXICITY OF ALKALOIDS

In this review, the emphasis is placed on the cytotoxic properties of alkaloids and
their underlying modes of action. For other properties of alkaloids, see the
6 Michael Wink

Table II Molecular targets of alkaloids in neuronal signal transduction (10–12,16)

Target Selected alkaloids

Neuroreceptor
Muscarinic acetylcholine Hyoscyamine and other tropane alkaloids; arecoline;
receptor berbamine and other isoquinoline alkaloids;
sparteine and other quinolizidine alkaloids;
cryptolepine; pilocarpine
Nicotinic acetylcholine Nicotine; boldine and other aporphine alkaloids; C-
receptors toxiferine; coniine and other piperidine alkaloids;
cytisine and other quinolizidine alkaloids;
epibatidine; tubocurarine
Adrenergic receptors Berbamine, berberine, and other isoquinoline
alkaloids; cinchonidine and other quinoline
alkaloids; corynanthine, yohimbine, and other
indole alkaloids; emetine; ephedrine; ergometrine
and related ergot alkaloids
Dopamine receptor Ergocornine and related ergot alkaloids;
bulbocapnine and related aporphine alkaloids;
anisocycline, stylopine, and related protoberberine
alkaloids; salsolinol and related isoquinolines
GABA receptor Bicuculline, cryptopine, hydrastine, and related
isoquinoline alkaloids; securinine; harmaline and
related beta-carboline alkaloids
Glycine receptor Corymine, strychnine, and related indole alkaloids
Glutamate receptor Histrionicotoxin and related piperidines; ibogaine
and related indole alkaloids; nuciferine and related
aporphine alkaloids
Serotonin receptor Akuammine and related indole alkaloids;
annonaine, boldine, and related aporphine
alkaloids; berberine and related protoberberine
alkalodis; ergotamine, LSD, and related ergot
alkaloids; psilocybine, bufotenine, N,N-
dimethyltryptamine, and related indoles;
harmaline and related beta-carboline alkaloids;
kokusagine and related furoquinoline alkaloids;
mescaline; ibogaine and other monoterpene indole
alkaloids
Adenosine receptor Caffeine, theobromine, and other purine alkaloids
Opiate receptor Morphine and related morphinan alkaloids;
akuammine, mitragynine, ibogaine, and related
indole alkaloids
Acetylcholine esterase Galanthamine; physostigmine and related indole
alkaloids; berberine and related protoberberine
alkaloids; vasicinol and related quinazolines;
 Molecular Modes of Action of Cytotoxic Alkaloids 7

Table II. (Continued )

Target Selected alkaloids

huperzine; harmaline, and related beta-carboline

alkaloids; demissine and related steroidal
alkaloids
Monoamine oxidase Harmaline and related beta carbolines; carnegine,
salsolidine, O-methylcorypalline and related
isoquinoline alkaloids; N,N-dimethyltryptamine
and related indole alkaloids
Neurotransmitter uptake Ephedrine and related phenylalkyl amines;
(transporter) reserpine, ibogaine, and related indole alkaloids;
cocaine; annonaine and related aporphine
alkaloids; arecaidine; norharman and related beta-
carboline alkaloids; salsolinol and related
isoquinoline alkaloids
Na+, K+ channels Aconitine and related diterpene alkaloids;
veratridine, zygadenine, and related steroidal
alkaloids; ajmaline, vincamine, ervatamine,
mitragynine, and other indole alkaloids; dicentrine
and other aporphine alkaloids; gonyautoxin;
paspalitrem and related indoles; phalloidine,
quinidine, and related quinoline alkaloids;
sparteine and related quinolizidine alkaloids;
saxitoxin; strychnine; tetrodotoxin
Ca++ channels Ryanidine; tetrandrine, berbamine, antioquine, and
related bis-isoquinoline alkaloids; boldine; caffeine
and related purine alkaloids; cocaine; corlumidine
and other indole alkaloids
Adenylate cyclase Ergometrine and related ergot alkaloids; nuciferine
and related aporphine alkaloids
cAMP phosphodiesterase Caffeine and related purine alkaloids; papaverine;
chelerythrine, sanguinarine, and related
benzophenanthridine alkaloids; colchicine;
infractine and related indole alkaloids
Protein kinase A (PKA) Ellipticine and related indole alkaloids
Protein kinase C (PKC) Cepharanthine and related bis-isoquinoline
alkaloids; michellamine B and related isoquinoline
alkaloids; chelerythrine and related
benzophenanthridine alkaloids
Phospholipase (PLA2) Aristolochic acid and related aporphine alkaloids;
berbamine and related bis-isoquinoline alkaloids
8 Michael Wink

previous reviews (3,7,8,10,11). The body of information regarding the cytotoxic

activities of SM and alkaloids is fast-growing since many compounds have been,
and are presently, being screened in many academic and industrial laboratories
for potential anticancer and antiviral activities. Data published during the last
12 years (i.e., after the 1993 review; 10) are so numerous (more than 1,000 entries
in data bases) that a tabulation would be beyond the scope of this review. Rather,
this review will highlight the molecular modes of action that underlie the cyto-
toxicity of alkaloids. Cytotoxic compounds are potentially interesting directly on
their own or as lead compounds for the development of new anticancer drugs,
for drugs against parasites, such as trypanosomes and Plasmodium sp. (12,15),
and against viral infections.

IV. MOLECULAR MODES OF ACTION OF CYTOTOXIC ALKALOIDS

Cytotoxicity occurs as a result of the molecular interactions of an alkaloid with

one or several important targets present in a cell (Figures 1 and 2). The main
targets include DNA, RNA, and the associated enzymes and processes (i.e., repli-
cation, repair, transcription, DNA polymerase, RNA polymerase, reverse transcri-
ptase, repair enzymes, topoisomerase, telomerase), protein biosynthesis,
protein conformation, biomembranes, and membrane proteins (for reviews,
see (10,11,16)).
Cell biologists distinguish between necrotic and apoptotic cell death. If a cell
is lysed by saponins or other detergents, or when it is mechanically wounded or
exposed to physical stress (heat, freezing, hypoxia) then it dies quickly by
necrosis. Although macrophages have to rush in to clear away the debris, often
an inflammation results. Apoptosis, or programmed cell death, was discovered
about 35 years ago in 1972 by Kerr, Wyllie, and Currie (17), and is a central
mechanism in the development of most organisms. The pathway functions
naturally to generate shapes and to control the number of cells in various tissues.
Apoptosis is characterized by nuclear chromatin condensation, cytoplasmic
shrinking, a dilated endoplasmic reticulum, membrane blebbing, and the for-
mation of apoptotic bodies. Programmed cell death is clean, quick, and involves a
predictable sequence of structural changes that cause a cell to shrink and to be
rapidly digested by macrophages or neighboring cells.
Apoptosis can be induced by many substances, among them several natural
products, such as alkaloids, that primarily interact with an important molecular
target such as DNA or microtubules. Most of the anticancer drugs presently used
in cancer therapy lead to apoptosis. The molecular targets associated with cell
death and cytotoxicity are discussed in the next section.

A. Interactions with DNA, RNA, and Associated Enzymes

1 DNA Alkylation and Intercalation

DNA is a central target of all organisms, which can be affected by certain
molecules (Figures 1 and 2). Some molecules can form covalent bonds with DNA
bases, the so-called alkylating agents. Alkylating compounds often attach to the
 Molecular Modes of Action of Cytotoxic Alkaloids 9

N6 of guanine. Some anticancer chemotherapeutic agents act as alkylating agents,

including cisplatin, nitrosourea derivatives, and nitrogen mustards. These com-
pounds lead to cytotoxicity by alkylating guanine units in their N6-position,
which eventually leads to strand breaks. Such modifications are removed by the
repair enzyme, alkylguanine–DNA alkyl transferase (AGT). In this process, the
alkyl residue is transferred to a cysteine in the active site of the enzyme (18). If
these modifications are not repaired by the abundant and active repair enzymes
of a cell, mutations arise. These mutations include nucleotide exchanges (tran-
sitions, transversions) and deletions. Deletions are especially harmful, as they
result in frameshift mutations. The corresponding proteins (in coding genes) are
then translated in the wrong frame and result in nonsense proteins. Therefore,
frameshift mutations mostly lead to a loss of function. Several alkaloids with
alkylating properties have been described, among them pyrrolizidine alkaloids,
aristolochic acids, and cycasin are the most prominent cases (16) (Table III). These
alkaloids are known to be mutagenic and teratogenic, and may induce cancer
(10,11,16).
Intercalating compounds, that are planar and lipophilic, can insert between
base pairs and thereby stabilize the double helix in a way that the replication
and transcription process is disturbed. Intercalation usually leads to frameshift
mutations. If these mutations occur in the heterochromatin, which does not code
for genes, they are usually without much consequence. In protein coding genes,
a nucleotide exchange in the third codon position (a so-called silent mutation) is
also without much consequence because of the degenerated genetic code. How-
ever, a mutation which changes the amino acid sequence of a protein or which
influences promoters and other regulatory sequences can have detrimental
effects. These negative effects can include disregulation of metabolism, tumor
growth, or even cell death.
Intercalating compounds also directly inhibit DNA replication and transcrip-
tion. RNA is basically single stranded, but most RNA molecules have double-
stranded stem structures because of complementary base pairing. These
double-stranded regions can also be intercalated. Therefore, many intercalating
SM are also inhibitors of DNA and RNA polymerases, of reverse transcriptase,
and even of DNA topoisomerases and possibly telomerase.
Table III provides an overview of alkaloids that interfere with DNA, RNA,
and associated proteins. Alkaloids with a planar and polycyclic structure are
good candidates for DNA intercalation. Protonable ring nitrogens can stabilize
the alkaloid–DNA complex by binding to the negatively charged DNA surface
(19,20). Such properties are abundant in isoquinoline, quinoline, and indole
alkaloids that are synthesized from the aromatic amino acids phenylalanine,
tyrosine, and tryptophan (11,12,16).

2 DNA Topoisomerase I and II

DNA topoisomerase I and II play important roles in DNA replication and tran-
scription. Their inhibition usually leads to cell-cycle arrest and cell death
by apoptosis. During replication, DNA needs to be uncoiled. In order to avoid
torsions and rotations, DNA is cleaved by DNA topoisomerase I, which forms
 10
Table III Interaction of alkaloids with DNA, RNA, and associated proteins (for earlier papers, see refs. 10,11)

Alkaloid Source Effect References

Michael Wink
Alkaloids derived from tryptophan
Camptothecin Camptotheca acuminata DNA intercalator; topoisomerase I (80,81,83)
(Cornaceae) inhibitor; stabilization of topo I/
DNA/CPT complex; cell-cycle arrest
in G2/M phase; apoptosis induction
Cinchonine Cinchona sp. (Rubiaceae) DNA intercalation; inhibition of DNA (12,16)
polymerase, reverse transcriptase
Cinchonidine Cinchona sp. (Rubiaceae) DNA intercalation; inhibition of DNA (12,16)
polymerase, reverse transcriptase
Cryptolepine Cryptolepis sanguinolenta Intercalation of GC rich DNA, (82,84–87)
(Asclepiadaceae) inhibition of topoisomerase II
(stabilizes topo II-DNA complexes);
stimulates DNA cleavage, cell-cycle
arrest; apoptostic; forms G-
quadruplexes with telomeric DNA
Dercitin Dercitus (sponge) DNA intercalator; inhibitor of DNA (88)
polymerase
Dictamine Dictamnus sp. (Rutaceae) DNA intercalation; mutagenic (89)
Ellipticine Ochrosia elliptica DNA intercalator; inhibition of (16,19,90,91)
(Apocynaceae) topoisomerase II and telomerase;
apoptotic; mutagenic
Evolitrine Rutaceae DNA intercalation; mutagenic (89)
g-Fagarine Rutaceae DNA intercalation; mutagenic (89)
Harmine Peganum harmala DNA intercalation; inhibition of (12,16,92–95)
(Zygophyllaceae) topoisomerase I; antitumor activity;
DNA strand break induction;
inhibition of DNA polymerase and
reverse transcriptase
Harmaline Peganum harmala DNA intercalation; inhibition of DNA (12,16)
(Zygophyllaceae) polymerase and reverse transcriptase
10-Hydroxy-camptothecin Camptotheca acuminata Topoisomerase I inhibitor; cell-cycle (78,79)
(Cornaceae) arrest in G2/M phase; apoptosis
induction
 Kokusaginine Rutaceae DNA intercalation; mutagenic (89)
Luotonine A Peganum nigellastrum Inhibitor of topoisomerase I; cytotoxic (96)
(Zygophyllaceae)
Maculine Rutaceae DNA intercalation; mutagenic (89)
Matadine Strychnos gossweileri DNA intercalation; topoisomerase II (25)
(Loganiaceae) inhibition
Neocryptolepine Cryptolepis sanguinolenta Intercalation of GC-rich DNA; (86,97,98)
(Asclepiadaceae) topoisomerase II inhibition; cytotoxic,
antibacterial, antiparasitic
Norharman Peganum harmala DNA intercalation; inhibition of DNA (12,16)
(Zygophyllaceae) polymerase and reverse transcriptase
Quinine Cinchona sp. (Rubiaceae) DNA intercalation; inhibition of DNA (12,16)
polymerase and reverse transcriptase
Quinidine Cinchona sp. (Rubiaceae) DNA intercalation; inhibition of DNA (12,16)
polymerase, reverse transcriptase
Serpentine Rauwolfia serpentina DNA intercalation; topoisomerase II (25)

Molecular Modes of Action of Cytotoxic Alkaloids

(Apocynaceae) inhibition
Skimmianine Rutaceae DNA intercalation; mutagenic (89)
Tangutorine Nitraria tangutorum Induction of cyclin kinase inhibitor p21; (99)
(Zygophyllaceae) inhibition of topoisomerase II
expression
Usambarensine Strychnos usambarensis DNA intercalator; apoptotic; cytotoxic, (25)
(Loganiaceae) antiparasitic
Alkaloids derived from phenylalanine/tyrosine
Actinodaphnidine Cassytha filiformes (Lauraceae) DNA intercalation; inhibition of (100)
topoisomerases; cytotoxic,
antitrypanosomal activity
Aristolactam glucoside Aristolochia sp. DNA intercalator (101–103)
(Aristolochiaceae)
Aristolochic acid Aristolochia sp. Activation by NADPH:CYP reductase (16,104)
(Aristolochiaceae) leading to formation of DNA
adducts; mutagenic and carcinogenic
Berbamine Berberis sp. (Berberidaceae) DNA intercalation; inhibition of DNA (12,16)
polymerase, reverse transcriptase

11
 12
Table III (Continued )

Alkaloid Source Effect References

Michael Wink
Berberine Berberis sp. (Berberidaceae) DNA intercalation; binding to single (12,16,20,105–107)
stranded poly (rA); inhibitor of
topoisomerase I and II; inhibition of
DNA polymerase, reverse
transcriptase
Berberrubine Berberis sp. (Berberidaceae) DNA intercalator; topoisomerase II (107–111)
inhibitor (stabilizing topo II cleavable
complexes); inhibition of catalytic
activity
Boldine Peumus boldo (Monimiaceae) DNA intercalation; inhibition of DNA (12,16,100,112)
polymerase, reverse transcriptase
Bulbocapnine Corydalis sp. (Fumariaceae) DNA intercalation (100,112)
Burasaine Burasaia sp. Probably DNA intercalation; cytotoxic (49)
(Menispermaceae)
Cassythine Cassytha filiformes (Lauraceae) DNA intercalation; inhibition of (100)
topoisomerases; cytotoxic;
antitrypanosomal activity
Chelerythrine Chelidonium majus When activated by CYP, DNA adducts (104)
(Papaveraceae) can be generated
Coptisine Ranunculaceae DNA intercalator (111,113)
Coralyne Papaveraceae DNA intercalator (GC rich sequences), (114–117)
topoisomerase I inhibitor
Dicentrine Dicentra sp. (Fumariaceae) Minor groove DNA intercalator; (16,100,112,118)
inhibition of topisomerase II;
mutagenic
Dicentrinone Ocotea leucoxylon (Lauraceae) Inhibitor of topoisomerase I (119)
Ecteinascidin 743 Ecteinascidia turbinate DNA alkylation; covalent bonding with (120,121)
(tunicate) 20 -amino group of guanine; cell-cycle
arrest
Emetine Psychotria ipecacuanha DNA intercalation; inhibition of DNA (12,16)
(Rubiaceae) polymerase, reverse transcriptase,
and protein biosynthesis; apoptotic
Epiberberine Coptis chinensis Inhibitor of topoisomerase (110)
(Ranunculaceae)
Fagaronine Fagara zanthoxyloides Major groove DNA intercalator; (122–125)
(Rutaceae) inhibition of topoisomerase I and II;
antitumor
Glaucine Papaveraceae DNA intercalation (100)
Groenlandicine Coptis chinensis Inhibition of topoisomerase I (110)
(Ranunculaceae)
Haemanthamine Lycoris radiata Complex formation with RNA (126)
(Amaryllidaceae)
Isocorydine Papaveraceae DNA intercalation (100,112)
Jatrorrhizine Ranunculaceae DNA intercalator (111,113)
Liriodenine Cananga odorata (Annonaceae) Inhibition of topoisomerase II (catalytic (16,127)
inhibitor); mutagenic
Lycobetaine Amaryllidaceae Inhibition of topoisomerase II; cytotoxic (128)
Lycorine Narcissus sp. Complex formation with RNA (126)

Molecular Modes of Action of Cytotoxic Alkaloids

(Amaryllidaceae)
Nitidine Toddalia asiatica (Rutaceae) DNA intercalator; inhibition of (124,129)
topoisomerase I and II; antitumor
compound
Palmatine Ranunculaceae DNA intercalator (111,113)
Roemerine Roemeria sp. (Papaveraceae) Mutagenic (16)
Salsolinol Salsola sp. (Chenopodiaceae) In combination with Cu(II) causes DNA (130)
strand breaks; ROS formation;
cytotoxic
Sanguinarine Sanguinaria canadensis DNA intercalator; intercalation of (12,16,104,106,113,131–
(Papaveraceae) double stranded GC-rich RNA; when 135)
activated by CYP, DNA adducts can
be generated; inhibition of DNA
polymerase, reverse transcriptase;
clastogenic; mutagenic
Tetrandrine Stephania tetrandra DNA alkylating; mutagenic; (16)
(Menispermaceae) carcinogenic; apoptotic

13
 14
Table III (Continued )

Alkaloid Source Effect References

Michael Wink
Alkaloids derived from ornithine/arginine
Clivorine Ligularia hodgsonii Metabolic activation by CYP3A1 and (136,137)
(Asteraceae) CYP3A2;
Monocrotaline Crotalaria sp. (Fabaceae) CYP3A substrate; CYP oxidation gives (138–140)
dehydromonocrotaline which forms
DNA–DNA interstrand and DNA–
protein cross-links
Pyrrolizidine alkaloids Asteraceae, Boraginaceae Metabolic activation by CYP3A; (16,138,141,142)
generation of reactive
dehydropyrrolizidines that can
alkylate DNA; DNA–DNA
interstrand and DNA–protein cross-
link formation; mutagenic,
carcinogenic
Miscellaneous alkaloids
Acronycine Acronychia baueri (Rutaceae) DNA alkylation; intercalator; (144–148)
carcinogen, apoptotic
Actinomycin D Streptomyces sp. DNA intercalating; inhibitor of DNA (22)
polymerase, apoptotic;
antineoplastic, antimicrobial
Ascididemin Cystodytes dellechiajei DNA intercalation; inhibition of (85,149–152)
(ascidian) topoisomerase II; SH-dependent
oxidative DNA cleavage
Batzelline D Zyzzya fuliginosa (sponge) Topoisomerase II inhibitor (153)
Cycasin Cycas and related Cycadaceae Activated methylazoxymethanol is a (16)
DNA methylating agent, i.e.
mutagenic and carcinogenic
Cystodytin A, J Cystodytes sp. (ascidian) DNA intercalator; topoisomerase II (154)
inhibitor; cytotoxic
Eilatin Cystodytes sp. (ascidian) DNA intercalator; topoisomerase II (77)
inhibitor; cytotoxic
Kuanoniamine Cystodytes sp. (ascidian) DNA intercalator; topoisomerase II (154)
inhibitor; cytotoxic
Lamellarin Lamellaria (mollusk) DNA intercalator; inhibitor of (73,155–157)
topoisomerase I
Lobeline Lobelia sp. (Campanulaceae) DNA intercalation; inhibition of DNA (12,16)
polymerase, reverse transcriptase
Mahanine, murrayanol Murraya koenigii (Rutaceae) Inhibition of topoisomerase I and II; (158)
antimcrobial and molluscicidal
activities
Makaluvamine A, F Zyzzya fuliginosa (sponge) DNA intercalator; topoisomerase II (73,159)
inhibitor; cytotoxic; antitumor
activity
Popolophuanone F marine sponges Inhibitor of topoisomerase II (160)
Prodigiosin Serratia marcescens (Bacteria) DNA intercalator; inhibition of (161)
topoisomerase I and II; induction of
apoptosis

Molecular Modes of Action of Cytotoxic Alkaloids

Shermilamine Cystodytes sp. (ascidian) DNA intercalator; topoisomerase II (154)
inhibitor; cytotoxic
Tsitsikammamine Tsitsikamma pedunculata DNA intercalator; topoisomerase I (162)
(sponge) inhibitor

15
16 Michael Wink

single-strand nicks. This enzyme is an important target in tumor cells, which is

also affected by some alkaloids, such as camptothecin and derivatives that are
important chemotherapeutic agents in tumor treatment (21). DNA topoisomerase
II cleaves and religates both DNA strands.
Drugs that attack topoisomerases either inhibit the enzymes (catalytic inhib-
itor) or they stabilise the fragile and normally transient ‘‘cleavable ternary
complexes’’ by preventing religation. Such complexes are converted to lethal
lesions when the cell tries to use the damaged DNA templates (22–24). The DNA
intercalating alkaloids cryptolepine, matadine, and serpentine tightly bind DNA
and stabilize the DNA–topoisomerase-II complex. In this way, they stimulate the
cleavage of DNA by topoisomerase II (25). Intercalators with a ‘‘deep interca-
lation mode’’ mainly affect topoisomerase I, whereas drugs with an ‘‘outside
binding mode’’ are topoisomerase II inhibitors (23). A number of alkaloids affect
both topoisomerase I and II, such as certain benzophenanthridine, pyridoindole,
indenoquinolone, and acridine alkaloids (23). Table III lists the alkaloids that
have been reported to interfere with DNA topoisomerases. As mentioned above,
many of these alkaloids have alkylating and intercalating properties.

3 Telomeres and Telomerase

Chromosomes are bordered by telomeres. The telomeres are made of tandem
repeats of short DNA sequences such as TTAGGG. They are added to the
chromosomes by telomerase, which is a reverse transcriptase and uses a RNA
template as a primer (Figure 3). Telomeres comprise between 5000 and 10,000
nucleotides and appear to protect the chromosomes from the attack of exonuc-
leases, from recombination and end-to-end fusion. The 30 -end of telomeres
consists of 100 to 200 unpaired bases (26). Since telomeres are guanidine-rich,
they have the possibility to form stacked guanine quadruplexes by Hoogsten-
hydrogen-bonding (27). Telomerase is only active in embryonic, stem, and germ-
line cells. In somatic cells it is turned off, with the consequence that telomere
lengths get shorter and shorter following cell division and during life. It is spec-
ulated that aging and death result when telomeres become too short, so that
essential genes are destroyed by exonucleases. Although primary cell cultures
cannot be maintained in cultivation for more than 70 cell divisions, cancer cells
are immortal and can be cultivated for dozens of years. The obvious difference is
due to the fact that telomerase is still active in many cancer cells, but silent in
primary cultures. About 80–85% of tumors express telomerase (28). Thus telomer-
ase is associated with cell immortality and cancer, which might be connected with
the ability of telomerase to prevent apoptosis by stabilizing telomeres.
This observation has triggered the search for compounds that can inhibit
telomerase. Special attention has been given to G-quadruplexes, since telomeres
that form stabilized quadruplexes cannot be elongated by telomerase (29).
Several intercalating compounds stabilize G-quadruplexes and thus inhibit telo-
merase; among these compounds are acridine alkaloids and anthraquinones
(30–32). Recently, some natural alkaloids were found, that can inhibit telomerase.
These include ellipticine, a known intercalating substance and experimental anti-
cancer agent. Ellipticine and 9-hydroxyellipticine interact with topoisomerase II
 Molecular Modes of Action of Cytotoxic Alkaloids 17

centromer

chromosome

telomeres

Chromosomal- Telomerase with RNA template

ends
3‘
TTAGGGTTAGGGTTAGGGTTA
AATCCC ATCCCAAT
5‘

TTAGGGTTAGGGTTAGGGTTAGGGTTAGGGTTAGGGTTA
AATCCC ATCCCAAT

TTAGGGTTAGGGTTAGGGTTAGGGTTAGGGTTAGGGTTAGGGTTAGGGTTA
AATCCC AATCCCAATCCCAATCCCAATCCCAATCCCAATCCCAAT

DNA-Polymerase

Figure 3 Schematic outline of telomeres and telomerase action.

and telomerase (19,33). Cryptolepine, neocryptolepine, and the bis-dimethylamino-

ethyl derivative of quindoline (a quinoline alkaloid) from Cryptolepis sanguinolenta
(Asclepiadaceae) recognize triplex and quadruplex DNA structures. They are weak
telomerase inhibitors with modest cytotoxicity (34,35). Also, the well-established
DNA intercalating protoberberine alkaloids, such as berberine, act as moderate
telomerase inhibitors (36). From marine sources, dictyodendrins A–E have been
isolated from the sponge Dictyodendrilla verongiformis, and are strong telomerase
inhibitors (37).
Telomerase is a relatively new drug target. It might be of some interest
to evaluate intercalating and G-quadruped stabilizing compounds for their
potential telomerase inhibiting activity.

B. Interactions with the Cytoskeleton

During cell division, the duplicated chromatids that are localized in the equa-
torial plane have to be separated and pulled apart into the daughter cells. This
process is achieved by a complex interaction of microtubules. Microtubules are
elements of the cellular cytoskeleton and are polymers of tubulin. Tubulin dimers
form protofilaments when GTP is present and several protofilaments organize
themselves into microtubules. When GDP dominates, the microtubules
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