Pyrrolizidine Alkaloid

Pyrrolizidine alkaloids (PAs) are a typical class of plant secondary metabolites, which
certain butterflies and moths in particular groups, that is, Danainae, Ithomiinae
(Nymphalidae), and Arctiidae, sequester as larvae or adults and utilize as chemical
defensive substances against predatory enemies, probably due to their bitter taste
and hepatotoxicity.13

From: Comprehensive Natural Products II, 2010

Related terms:

Chemistry, Swainsonine, Alkaloid, Ion, Pyrrolizidine, Heterocyclic Compound, Sul-

fonium

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Pyrrolizidine Alkaloids
Joaquín Tamariz, ... Francisco Delgado, in The Alkaloids: Chemistry and Biology,
2018

Abstract
Naturally occurring pyrrolizidine alkaloids (PAs) are isolated from plants and other
sources. The interest of the scientific community in these compounds owes itself to
their high toxicity and biological activity, as well as to the challenge of synthesizing
their pyrrolizidine scaffold. This review encompasses a wide range of topics found
in the literature from 1995 to date, including the occurrence, biosynthesis, toxicity
(hepatotoxicity, genotoxicity, and tumorigenicity), biological activity, and pharma-
cological properties (glycosidase inhibitory activity) of these secondary metabolites.
Particular attention is given to the chemistry of PAs, addressing general strategies
for formal and total syntheses via amino-based substrates, pyrroles, and pyrroli-
dine-based derivatives.
> Read full chapter

Biological Significance of Alkaloids

Carl von Linné, in Alkaloids - Secrets of Life, 2007

3.6 Aberrations in cells

Pyrrolizidine alkaloids are toxic to foreign organisms (Figure 89). This problem was
largely studied in the 1960s–1980s493, 494, 495, 496, 497, 498, 499, 500. Serious livestock
poisoning episodes are mentioned in literature from the effects of the pyrrolizidine
alkaloid of the Senecio genus especially Senecio riddellii, Senecio douglasii and Senecio
jacobaea471. The toxicity of pyrrolizidine alkaloids to livestock was considered coinci-
dental. Johnson and Molyneux501 and Johnson et al.502 have stated that experimental
feedings of pyrrolizidine alkaloids to cattle empirically proved that the threshold
level of ingesting alkaloids must be excessive for toxicity to occur. On the other
hand, there are also known cases of animal poisoning from pyrrolizidine alkaloids
found in Cynoglossum officinale (Boraginaceae). Baker et al.503 have reported cases
of calves being poisoned, and Knight et al.504 connected the deaths of two horses
to poisoning by pyrrolizidine alkaloids. The acute toxicity of these alkaloids varies
widely; it is recognized by the International Programme on Chemical Safety (IPCS)
that for rats the LD50 of most alkaloids is 34–300 mg kg−1 475. Lasiocarpine doses
equivalent to 0.2mgkg−1 body weight per day lead to the development of tumours
in rats. For pigs, 1.8mgkg−1 doses cause chronic liver damage. For humans, the
lowest reported intake level causing veno-occlusive disease (VOD) is estimated to
be 0.015 mg kg−1 body weight per day475. Some pyrrolizidine alkaloids are thought
to cause lung damage, affect blood pressure and lead to secondary effects of the
functioning of the right side of the heart. Moreover, according to the WHO data,
pyrrolizidine alkaloids produce chromosomal aberrations in mammalian cells. Some
pyrrolizidine alkaloids and their N-oxides are active as tumour inhibitors500. They
also can induce genetic changes and produce cancer in the livers of rats. The toxic
effects of these alkaloids can be acute or chronic. Toxicity laboratory trials with
retrorsine reported by White et al.505 resulted in centrilobular necrosis in rats, mice
and guinea pigs, periportal necrosis in hamsters and focal necrosis in fowl and in
monkeys. Even in the 1940s, Wakim et al.506 reported that senecionine produces
necrosis in the periportal and midzonal areas of liver lobules. Later, Dueker et al.453
studied monocrotaline metabolism using rat and guinea pig hepatic microsomes.
These results suggest that guinea pigs are resistant to pyrrolizidine alkaloid toxicity.
Esterase hydrolysis was observed in the metabolism of the guinea pig, and in the
case of rats, there was no esterase activity. This explains the guinea pig's resistance
to pyrrolizidine alkaloid toxicity. Monocrotaline was also researched by Vaszar et
al.459 Their results showed statistically significant increases in proteases in rats as a
result of the activity of this alkaloid toxin. Moreover, Smith et al.458 have researched
pyrrolizidine alkaloid toxicity in horses. They concluded that these alkaloids led
to chronic active hepatitis and furthermore chronic heart damage, including right
ventricular hypertropy as a consequence of pyrrolizidine lung damage. However, it
is important to note that pyrrolizidine alkaloid toxicity depends on alkaloid structure
and its possible reduction. The mechanism of toxic activity of these alkaloids is con-
nected to metabolism in the parenchymal cells, where pyrrolizidine alkaloids change
to pyrroles acting on hepatocytes and blood vessels in the liver or lungs. McLean507
reported that as a consequence of this, disaggregation of polyribosomes, absence of
pyruvate oxidation and lysosomal activity and necrosis occur. It is important to note
that pyrrolizidine alkaloids are inactive as a cell poison by themselves.

Figure 89. Acute toxicity (LD50) of some pyrrolizidine alkaloids in male rats.

(Sources: Refs [472, 473, 474, 475]).

> Read full chapter

Biology of alkaloids
Dr.Tadeusz Aniszewski, in Alkaloids (Second Edition), 2015

3.3.6 Aberrations in cells

Pyrrolizidine alkaloids are toxic to foreign organisms (Figure 3.13). This problem
was largely studied in the 1960s–1980s.39,53,72,121,182,228,234,270 Serious livestock poi-
soning episodes are mentioned in literature from the effects of the pyrrolizidine
alkaloid of the Senecio genus, especially Senecio riddellii, Senecio douglasii, and
Senecio jacobaea.201 The toxicity of pyrrolizidine alkaloids to livestock was considered
coincidental. Johnson and Molyneux133 and Johnson, Molyneux, and Stuart134 stated
that experimental feedings of pyrrolizidine alkaloids to cattle empirically proved that
the threshold level of ingesting alkaloids must be excessive for toxicity to occur. On
the other hand, known cases of animal poisoning from pyrrolizidine alkaloids are
found in Cynoglossum officinale (Boraginaceae). Baker et al.27 reported cases of calves
being poisoned, and Knight et al.144 connected the deaths of two horses to poisoning
by pyrrolizidine alkaloids. The acute toxicity of these alkaloids varies widely; it is
recognized by the International Programme on Chemical Safety (IPCS) that for rats
the LD50 of most alkaloids is 34–300 mg kg− 1.304 Lasiocarpine doses equivalent to
0.2 mg kg− 1 body weight per day lead to the development of tumors in rats. For pigs,
1.8 mg kg− 1 doses cause chronic liver damage. For humans, the lowest reported
intake level causing veno-occlusive disease (VOD) is estimated to be 0.015 mg kg− 1
body weight per day.304 Some pyrrolizidine alkaloids are thought to cause lung
damage, affect blood pressure and lead to secondary effects of the functioning of
the right side of the heart. Moreover, according to the WHO data, pyrrolizidine
alkaloids produce chromosomal aberrations in mammalian cells. Some pyrrolizidine
alkaloids and their N-oxides are active as tumor inhibitors.270 They also can induce
genetic changes and produce cancer in the livers of rats. The toxic effects of these
alkaloids can be acute or chronic. Toxicity laboratory trials with retrorsine reported by
White, Mattocks, and Butler309 resulted in centrilobular necrosis in rats, mice, and
guinea pigs; periportal necrosis in hamsters; and focal necrosis in fowl and monkeys.
Even in the 1940s, Wakim, Harris, and Chen296 reported that senecionine produces
necrosis in the periportal and midzonal areas of liver lobules. Later, Dueker et al.83
studied monocrotaline metabolism using rat and guinea pig hepatic microsomes.
These results suggest that guinea pigs are resistant to pyrrolizidine alkaloid toxicity.
Esterase hydrolysis was observed in the metabolism of the guinea pig, and in the
case of rats, there was no esterase activity. This explains the guinea pig’s resistance
to pyrrolizidine alkaloid toxicity. Monocrotaline was also researched by Vaszar et
al.291 Their results showed statistically significant increases in proteases in rats as
a result of the activity of this alkaloid toxin. Moreover, Smith et al.262 researched
pyrrolizidine alkaloid toxicity in horses. They concluded that these alkaloids led to
chronic active hepatitis and, furthermore, chronic heart damage, including right
ventricular hypertrophy as a consequence of pyrrolizidine lung damage. However, it
is important to note that pyrrolizidine alkaloid toxicity depends on alkaloid structure
and its possible reduction. The mechanism of toxic activity of these alkaloids is con-
nected to metabolism in the parenchymal cells, where pyrrolizidine alkaloids change
to pyrroles acting on hepatocytes and blood vessels in the liver or lungs. McLean185
reported that, as a consequence of this, disaggregation of polyribosomes, absence
of pyruvate oxidation, and lysosomal activity and necrosis occur. It is important to
note that pyrrolizidine alkaloids are inactive as a cell poison by themselves.
 Figure 3.13. Acute toxicity (LD50) of some pyrrolizidine alkaloids in male mice.

Sources: Refs. 52,120,181,304.

> Read full chapter

Fused Five- and Six-membered Rings

with Ring Junction Heteroatoms
Wilhelm Flitsch, in Comprehensive Heterocyclic Chemistry II, 1996

8.01.11 Important Compounds and Applications

Pyrrolizidine alkaloids are widespread in nature. New results in this field are reported
annually 93MI 801-02 . General reviews B-85MI 801-01,B-90MI 801-01, 87MI
801-01 as well as reviews on the toxicology 93MI 801-03 and the synthesis
88MI 801-02 of pyrrolizidine alkaloids have appeared.

2,3-Dihydro-1H-pyrrolizines are as proline specific Maillard products 85MI

801-01 .

Some pyrrolizidine derivatives are medically useful. 3,5-Dioxopyrrolizidine (158)

(Rolziacetam, CI-911) is a cognition activator of the nootropic class. 87JMC498 .
Compounds of this type have the potential in treating disorders of learning and
memory, for example Alzheimer’s disease, age-associated memory impairment and
other forms of senile cognitive decline. Background information is given by Moos
et al. 88MI 801-01 .

The antitumor activity of pyrrolizidine derivatives is noteworthy. A proof has been

given that these antitumor compounds act by interstrand cross-linking 93JA3407 .
Most important are mitomycins, which are treated in Section 8.01.10.

> Read full chapter

Hepatic Toxicology
S.B. Yee, R.A. Roth, in Comprehensive Toxicology, 2010

Pyrrolizidine alkaloid (PA)-containing plants are widely distributed throughout the

world and are among the most common poisonous plants affecting livestock,
wildlife, and humans. In particular, PAs have been responsible for considerable
human morbidity and mortality as a result of inadvertent consumption of PA-cont-
aminated food sources or through the intentional ingestion of PA-containing alter-
native medicines. Although primarily known for hepatotoxicity, often marked by the
development of hepatic veno-occlusive disease, PAs may also induce extrahepatic
toxicities and potentially carcinogenesis. PAs represent a significant risk to livestock
and human health that often is underreported due to difficulties in determining
the etiology of PA exposure and correctly diagnosing PA toxicity. Although there
is no definitive treatment for PA toxicity, prevention and monitoring are critical
to reducing PA exposure. This chapter provides a brief review of the chemistry,
exposure, metabolism, and pathogenesis of PAs.

> Read full chapter

Hepatic Toxicology
J.P. Luyendyk, ... P.E. Ganey, in Comprehensive Toxicology, 2010

9.13.5.1.2 Monocrotaline
Pyrrolizidine alkaloids (PAs) are plant toxins to which humans have been exposed
through herbal remedies. Many PAs, such as monocrotaline (MCT), are hepatotoxic
to animals and have been responsible for liver injury in people who consumed
medicaments containing them (see Chapter 9.28 for more details on PA-mediated
hepatotoxicity). Administration to rats of a small, noninjurious dose of LPS shortly
before or after a small, nontoxic dose of MCT led to liver injury (Yee et al. 2000). The
resultant hepatocellular necrosis was not due to direct interaction of the two agents
in HPCs but to an activated innate immune system. Hepatic PMN accumulation
and prolonged plasma TNF elevation occurred in MCT–LPS-cotreated rats, and
hepatocellular necrosis was markedly reduced either by prior depletion of PMNs or
by neutralization of TNF (Yee et al. 2003a,b). Injury to sinusoidal endothelium was
an early event associated with activation of the hemostatic system and deposition of
fibrin in sinusoids. Pretreatment of MCT–LPS-coexposed rats with anticoagulants
prevented the damage to parenchymal as well as sinusoidal ECs (Copple et al. 2002).
Thus, available evidence pointed to sinusoidal EC injury coupled with a cascade of
inflammatory events as crucial to the hepatotoxic interaction between MCT and LPS.

> Read full chapter

Alkaloids Derived from Ornithine and

Arginine
In Alkaloids, 2015

Most pyrrolizidine alkaloids are esters constructed from an aminoalcohol called a

necine unit (pyrrolizidine derivative), and straight or branched chain fatty acid, called
a necic acid. Necine is the derivative of pyrrolizidine, i.e., azabicyclo[3,3,0]octane, and
a hydroxymethyl (–CH2OH) moiety is always attached at the C-1 position. Necines
can be classified into two groups, either with or without a double bond between the
C-1 and C-2 positions. The stereochemistry of the H-8 position is usually H-8 .
When the C-8 position is oxidized, as in the case of otonecine, it becomes an
eight-membered ring by decyclization.

> Read full chapter

New Approaches to the Syntheses of

Piperidine, Izidine, and Quinazoline Al-
kaloids by Means of Transition Metal
Catalyzed Carbonylations
Iwao Ojima, Donna M. Iula, in Alkaloids: Chemical and Biological Perspectives, 1999

1 INTRODUCTION
Piperidine, pyrrolizidine, indolizidine, quinolizidine, and quinazoline alkaloids are
found in great numbers in nature. Because of their diverse biological activities, these
alkaloids have attracted the attention of synthetic, medicinal, pharmaceutical, and
organic chemists. Numerous methodologies for constructing piperidine and izidine
alkaloids have been developed over the years. In this regard, it can be said that these
alkaloids, as synthetic targets, have contributed to the growth and development
of modem organic syntheses. Although there are many synthetic strategies in the
literature, this chapter will focus on transition metal-catalyzed carbonylations as
efficient and novel approaches toward the construction of alkaloid skeletons.

The development of synthetic methods by means of transition metal-catalyzed

reactions over the last decade or two has been explosive [1,2]. Transition metal
catalysts facilitate complex organic transformations with high degrees of chemo-,
regio-, and stereoselectivity. In general, carbonylations are transition metal-cat-
alyzed reactions that use carbon monoxide, involving the incorporation of a carbonyl
group into a substrate [3]. For example, the hydroformylation reaction is one of the
most important industrial processes for the production of aldehydes from alkenes.
Carbonylations are also used for the homologation of a variety of organic substrates,
a process which is very useful in organic synthesis. Carbonylation reactions are very
“tunable” in that changes in transition metal catalyst, ligands, and reaction condi-
tions can exert substantial effects upon the chemo-, regio-, and stereoselectivity of
the process.

This chapter describes the recent advances in the synthesis of piperidine, izidine,
and quinazoline alkaloids by means of transition metal-catalyzed carbonylations.

> Read full chapter

Integrative Plant Biochemistry

Nailish Samanani, Peter J. Facchini, in Recent Advances in Phytochemistry, 2006

Pyrrolizidine Alkaloids
The constitutively expressed pyrrolizidine alkaloids (PAs) comprise a diverse group
of over 350 structures with scattered occurrence in certain higher plant taxa. Their
occurrence is mostly restricted to the Asteraceae (e.g., the genera Senecio and Eupa-
torium), many genera of the Boraginaceae, a few genera of the Fabaceae, and certain
genera of the Orchidaceae.90 The necine base of PAs is thought to originate from
ornithine or arginine, whereas the necic acid moiety originates from aliphatic amino
acids such as isoleucine.90 For most herbivores, PAs are strong feeding deterrents
and liver toxins in vertebrates.91 In plants of Senecio species, senecionide N-oxide
is synthesized in the roots and transported to the preferential sites of storage, the
inflorescences and peripheral tissues of the leaves and stems, via the phloem. In
some species of Senecio, 60 to 80% of the PAs are found in the inflorescences,
which represents concentrations 10- to 30-fold higher than in the vegetative organs
of the plant.92 In vegetative organs, they are found mostly in the epidermal and
subepidermal layers. Accumulation in reproductive and peripheral tissues of the
plant is consistent with their role as defense compounds. Remarkably, specialized
herbivorous insects from diverse taxa have evolved adaptations to not only overcome
the barriers posed by these toxic alkaloids but also to obtain and use them for their
own defense against predators.90

The first pathway-specific enzyme involved in the biosynthesis of homospermidine,

a precursor to the necine base moiety of pyrrolizidine alkaloids, is homospermi-
dine synthase (HSS). Sequence analysis of HSS revealed amino acid and nucleic
acid identities of 79% and 83%, respectively, to deoxyhypusine synthase (DHS),
an enzyme catalyzing the first step in the activation of a translation initiation
factor (eIF5A) essential for eukaryotic cell proliferation.93 Evidence suggests that in
pyrrolizidine alkaloid-producing plants the HSS gene evolved from the DHS gene
via gene duplication.93 RNA-blot, reverse transcriptase-PCR and immunolocalization
analyses showed that although DHS is constitutively expressed in the shoots and
roots of Senecio vernalis (Asteraceae), HSS expression is root specific.94 Furthermore,
HSS expression is restricted to distinct groups of endodermal and adjacent cortical
cells opposite the phloem (Fig. 3.1C). Thus, the expression pattern of HSS in S.
vernalis has undergone a drastic change from the ancestral DHS gene. In contrast,
HSS expression in Eupatorium cannabinum was observed to occur uniformly in all
cells of the root cortex parenchyma, but not in the endodermis and exodermis (Fig.
3.1D).95 These data, along with the scattered occurrence of pyrrolizidine alkaloids in
several plant families, suggest the independent chance recruitment of HSS from the
ubiquitous DHS gene in various angiosperm families.

> Read full chapter

Bicyclic 5-5 and 5-6 Fused Ring Systems

with at least One Bridgehead (Ring
Junction) N
H. Dhimane, G. Lhommet, in Comprehensive Heterocyclic Chemistry III, 2008

11.01.11 Important Compounds and Applications

Several water-soluble polyhydroxylated pyrrolizidine alkaloids isolated from plants
and microorganisms have been described; many of these are inhibitors of gly-
cosidases or glycotransferases. These enzymes that catalyze the hydrolysis of the
glycosidic linkage in biomolecules, such as carbohydrates and glycoconjugates, are
involved in a large variety of biological functions making them essential for all living
organisms <2001P265>. Therefore, these glycoprocessing enzymes are considered
as potential therapeutic targets in many diseases <2001P265>. Because of their lim-
ited availability, only few natural polyhydroxylated pyrrolizidines have been studied
for their therapeutic potential. Therefore, several hundred related pyrrolizidines were
synthesized; Zou reported a general review on the various methodologies developed
in these syntheses <2005MI1363>.

Dihydropyrrolizines and dihydropyrrolizinones are widely employed as scaffolds

in medicinal chemistry, and many drugs or drug candidates are based on these
skeletons.

Aryl-substituted pyrrolizinones 90 were examined for their potential as inhibitors of

the cytochrome P450 aromatase <2000BMC945>. Some benzo-annulated tetrahy-
dropyrrolizinones were evaluated as inhibitors of cyclin-dependent kinases (CDKS)
<2001JME4615>.

Ketorolac 132, a nonstereoidal anti-inflammatory drug with cyclooxygenase (COX)

inhibitory activity, was marketed as a racemic mixture. It is now well established
that (S)-ketorolac is the active enantiomer <1999MI382>. Therefore, efforts were
devoted to the selective synthesis of this active stereomer, either by enzymatic kinetic
resolution <2001TA1865> or by enantioselective synthesis <2005AGE609>.

ML-3000 (271a), also a nonstereoidal anti-inflammatory which acts as an in-

hibitor of cyclooxygenases (COX-1, COX-2) and 5-lipoxygenase (5-LOX) enzymes,
was intensively studied <1999T5145>. Several 6,7-diaryl-2,3-1H-dihydropyrrolizines
were synthesized and evaluated as inhibitors of COX-1, COX-2, and 5-LOX. From
this structure–activity relationship study, it was concluded that the balance of
COX-1/COX-2 and 5-LOX inhibition can be modulated by modifying the aro-
matic substituents at the 6- and 7-position of the dihydropyrrolizine scaffold
<2002EJM953, 2003WO018583>.

Dihydropyrrolizines 272, their salts and solvates, were prepared and evaluated as
potential antitumor drugs or as site-specific DNA alkylating agents in the gene-re-
lating technologies <1998WO9827095>.
 > Read full chapter

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