ERGOT ALKALOIDS

Name: Chetana Jadhav

Class: 1st yr M.Pharm.
+MBA (IP)
Roll no. : IP03
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ALKALOIDS

 Alkaloids are a group of naturally occuring

chemical
compounds that mostly contain basic nitrogen
atoms.
 Alkaloids are produced by a large variety of
organisms including bacteria, fungi, plants, and
animals.
 They can be purified from crude extracts of these
organisms by acid-base extraction

Sharma, Niti, Vinay Sharma, Hemanth Manikyam, and Acharya Krishna. “Ergot Alkaloids: A Review on Therapeutic Applications.” European Journal of
Medicinal Plants 14, no. 3 (2016): 1–17. https://doi.org/10.9734/ejmp/2016/25975.
 3

CHEMISTRY

Colour less
Crystalline
Non – volatile solids are soluble in organic
solvent
Insoluble in water

Sharma, Niti, Vinay Sharma, Hemanth Manikyam, and Acharya Krishna. “Ergot Alkaloids: A Review on Therapeutic Applications.” European Journal of
Medicinal Plants 14, no. 3 (2016): 1–17. https://doi.org/10.9734/ejmp/2016/25975.
 4

ERGOT ALKALOIDS

 Ergot alkaloids are nitrogen-containing natural

products belonging to indole alkaloids.

 The best known producers are fungi of the phylum

Ascomycota, e.g., Claviceps, Epichloë, Penicillium and
Aspergillus species.

Sharma, Niti, Vinay Sharma, Hemanth Manikyam, and Acharya Krishna. “Ergot Alkaloids: A Review on Therapeutic Applications.” European Journal of
Medicinal Plants 14, no. 3 (2016): 1–17. https://doi.org/10.9734/ejmp/2016/25975.
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Claviceps purpurae
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OCCURENCE
 Ergot alkaloids were first developed from the sclerotium
of the parasitic ascomycete Claviceps purpurae, which
developes on rye and other grasses.

 The term ERGOT is used to refer both to the fungus

developing in the rye plant and to the alkaloids which
are produced by the fungus.

 Presently there are 40 known ergot alkaloids

produced by various Claviceps strains.

Sharma, Niti, Vinay Sharma, Hemanth Manikyam, and Acharya Krishna. “Ergot Alkaloids: A Review on Therapeutic Applications.” European Journal of
Medicinal Plants 14, no. 3 (2016): 1–17. https://doi.org/10.9734/ejmp/2016/25975.
 Producers of alkaloids
Organism Plant host Alkaloid Alkaloids
content produced

Claviceps Rye wheat 0.1-0.5 Ergocornine

purpurae Ergocryptine
Ergosine
C. fusiforims Pennisetum 0.3 Chanoclavine
typhoids Elymoclavine
Ergometrine
C.gigantae Zea mays 0.03 Pyroclavine
Festuclavine

C.paspali Paspalum spp 0.003 D-Lysergic acid

α-Hydroxyethyl
lysergamide
Florea, Simona, Daniel G. Panaccione, and Christopher L. Schardl. “Ergot Alkaloids of the Family Clavicipitaceae.”
Phytopathology 107, no. 5 (2017): 504–18. https://doi.org/10.1094/PHYTO-12-16-0435-RVW.
PHARMACOLOGICAL PROPERTIES
• The nucleus common to all ergot alkaloids (lysergic acid) was isolated
and characterized in 1934 by Jacobs and Craig of the Rockefeller
Institute of New York .
• All the naturally obtained ergot alkaloids contain tetracyclic ergoline
ring system, which makes them structurally similar with other
neurotransmitters such as noradrenaline, dopamine or serotonin .
• This structure homology of ergot alkaloids with these
neurotransmitters implies that these alkaloids can be used for the
treatment of neuro related conditions like migraine, Parkinson’s
disease etc.
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PHARMACOLOGICAL PROPERTIES
 Stimulation of the sympathetic nervous system.
 Ergovanine is used to hasten labor and prevent postpartum
bleeding.
 Ergotamine is a compound produced by Claviceps purpurea
and is a powerful vasoconstrictor, which means it constricts the
blood vessels and thus the blood flow.
 A mixture of dihydrocompounds from ergocristine , ergocriptine ,
and ergocornine is used for treatment of disturbances of preipheral
and central circulation system.
 Dihydroergotamine and ergotamine are used to treat severe,
throbbing headaches, such as migraine and cluster headaches.
 Ergot alkaloids are effective in reducing blood loss and postpartum
haemorrhage.

Sharma, Niti, Vinay Sharma, Hemanth Manikyam, and Acharya Krishna. “Ergot Alkaloids: A Review on Therapeutic Applications.” European Journal of
Medicinal Plants 14, no. 3 (2016): 1–17. https://doi.org/10.9734/ejmp/2016/25975.
 8

DEVELOPMENT CYCLE
OF
CLAVICEPS
 7.
Sclerothium 1.
ripens within Ascospores
two months

6. Alkaloid 2. Infection
formation is of grass
initiated flowers

4. Asexual
spores
5. Filamentous excreted
mycelium is 3.Growth of
replaced by and no
filamentous
plecenchymatic mycelium in alkaloid
Smith, Courtland L. “The Life Cycle of Fisheries.” Fisheries 11, no. 4
tissue the ovary formation (1986): 20–25. https://doi.org/10.1577/1548-
8446(1986)011<0020:tlcof>2.0.co;2.
Structure
• Structurally the most common features of these alkaloids are methylation at
6th position of nitrogen and substitution at 8th position of carbon in the
tetracyclic ring system. Interestingly, due to asymmetric carbon atom at 8th
position, the 10- ergolens produce two epimers; ergolenes and isoergolenes
• Based on the substitution 8th position these alkaloids can be categorized
into four groups as
1. Clavine alkaloids
2. Lysergic acid derivatives
3. Ergopeptine alkaloids
4. Ergopeptam alkaloids
1. Clavine alkaloids: the hydroxy and dehydro
derivatives of 6,8- dimethylergolenes and the
corresponding ergolines. They also include
the chanoclavines with an open D-ring
between N-6 and C-7.

2. Lysergic acid derivatives: These derivatives

of lysergic acid are amides in which the
amidic moiety is formed by a small peptide or
an alkylamide. Nonpeptide amides of lysergic
acids isolated from ergot fungi are
ergometrine, lysergic acid 2-
hydroxyethylamide, lysergic acid amide, and
paspalic acid
3. Ergopeptine alkaloids: the unique feature of these
alkaloids is the cyclic part which is formed by the
reaction of an a-hydroxy-amino acid adjacent to lysergic
acid with a carboxyl group of proline. In addition these
ergot alkaloids are composed of lysergic acid and a
tripeptide moiety. The compounds usually formed by these
amino acids are ergotamine, ergotoxine, ergoxine, and
ergoannines

4. Ergopeptam alkaloids: have structure similar to

ergopeptines however the major difference between
them is the proline moiety i.e. D-proline (ergopeptam)
than L-proline (ergopeptines) and the tripeptide chain is
a noncyclol lactam. The examples are ergotamams,
ergoxams, ergotoxams, and ergoannams
Introduction to cultivation of
ergot alkaloids
• The industrial production of the ergot alkaloids began in 1918 when Arthur Stoll patented
the isolation of ergotamine tartrate, which was subsequently marketed by Sandoz in
1921.
• Sandoz dominated the world industrial market in ergot alkaloid production up until the
1950s, when other competitors begin to appear.
• Today Novartis (the successor to Sandoz) still retains leadership in the world production of
ergot alkaloids.
• Some other major producers of these alkaloids market their products as bulk
pharmaceutical chemicals, including:
Boehringer Ingelheim (Germany), Galena (Czech Republic), Gedeon Richter (Hungary),
Lek (Slovenia), and Poli (Italy).
• Others active in the marketplace include Eli Lilly and Farmitalia.
• Annual world production of ergot alkaloids has been estimated 
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Biosynthesis
 Alkaloids synthesis occurs upon the
endoplasmic reticulum in claviceps when it
is grown in submerged culture.
FORMATION OF ERGOMETRINE FROM
MEVALONATE

Mevalonate

Isopentenyl pyrophosphate

Dimethylallyl pyrophsphate
 Tryptophan

Dimethylallyl tryptophan

Chanoclavine

Agroclavine

Elymoclavine
 8,2 Lysergic acid

Lysergic acid

Lysegylalanine

Α-Hydroxyethyllysergamide

Ergometrine
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Production of ergot alkaloids

There are a number of methods of obtaining ergot

alkaloids:
 Chemical synthesis
 Culture of Claviceps strains on the respective
host
 Microbial fermentation
 Surface culture
 With immobilized cells
Culture on the host plant or in submerged culture are
the process most used commercially.
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Chemical synthesis

 Total chemical synthesis of ergot alkaloids is

possible, but currently this is not cost-effective.
 Lysergic acid which is produced fermentatively
can be chemically transformed into the desired
alkaloids.
 Ergoline derivatives used medically using this
method, with the exception of peptide bonds.
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Surface culture:
A process has been described for the large-
scale production of ergot alkaloids using
surface cultures of C.purpurae grown
under sterile conditions.
 The advantage of this process is that a
higher prportion of the more desirable
ergotamine and ergotoxine alkaloids are
formed.

Sastry, K S M, V R Pandotra, R N Thakur, J H Gupta, K P Singh, and A Husain. “Studies on Parasitic Cultivation of Ergot [Claviceps Purpurea (Fr.) Tul.] in
India.” Proceedings of the Indian Academy of Sciences - Section B 72, no. 3 (1970): 99–114. https://doi.org/10.1007/BF03050452.
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Semicontinuous transformation
with immobilized mycelium
 A process has been developed for semicontinuous
alkaloid production using immobilized
mycelium of Claviceps purpurae and
C.fusiformis.
 C.purpurae which forms Ergometrine and and
mixture of chanoclavin , agroclavin and
elymoclavin , the best results has been obtained
by immobilization in 4% calcium alginate gel.
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 Concentration of algine increases to 8% - yield of

alkaloid increased by 35%, but the main product
is agroclavin due to reduced Oxygen diffusion.
 To prevent contaminaton problem during the long
incubation period with the immobilized
mycelium, an antibiotic chloramphenicol was
added.
Production by 25

fermentation
 Three species of Claviceps are currently used in the
production of alkaloids by fermentation.
C.paspali
C.fusiformis
C.purpurae
 Submerged culture
produced about 20mg
alkaloid/l
 Strain development and culture medium optimization
resulted in a commercial process which had alkaloid
titres of 5g/l.
STAGES OF FERMENTATION26

Homogenized mycelium of
a 5-10day agar slant culture
conidium suspension

Growth in shake flask

Preculture

48 HOURS

Production culture
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Regulationn of alkaloid production

in cultures:

 To produce alkaloids the medium must contain an

organic acid of the TCA cycle or a related
compound as well as carbohydrate.
 Mannitol and succinate : production of lysergic acid.
 Sucrose and citrate : production of Ergotamine and
Ergocristine.
 Ergot alkaloid production exhibits a typical
phosphate regulation.
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 In the trophophase (3-4 days), after free phosphate is

used up, growth ceases and the culture enters the
idiophase.
 Tryptophan induces alkaloid synthesis and serves as a
precursor.
 In submerged culture, synthesis of the alkaloid is increased
considerably when aspargine is used as a Nitrogen source
instead of ammonium salts.
 References
• Sastry, K S M, V R Pandotra, R N Thakur, J H Gupta, K P Singh, and A Husain. “Studies on Parasitic Cultivation
of Ergot [Claviceps Purpurea (Fr.) Tul.] in India.” Proceedings of the Indian Academy of Sciences - Section B
72, no. 3 (1970): 99–114. https://doi.org/10.1007/BF03050452.

• Amici, A M, A Minghetti, T Scotti, C Spalla, and L Tognoli. “Production of Peptide Ergot Alkaloids in Submerged
Culture by Three Isolates of Claviceps Purpurea.” Applied Microbiology 18, no. 3 (September 1969): 464–68.
https://pubmed.ncbi.nlm.nih.gov/5373678
• .
•   Sharma, Niti, Vinay Sharma, Hemanth Manikyam, and Acharya Krishna. “Ergot Alkaloids: A Review on
Therapeutic Applications.” European Journal of Medicinal Plants 14, no. 3 (2016): 1–17.
https://doi.org/10.9734/ejmp/2016/25975.

• Florea, Simona, Daniel G. Panaccione, and Christopher L. Schardl. “Ergot Alkaloids of the Family Clavicipitaceae.”
Phytopathology 107, no. 5 (2017): 504–18. https://doi.org/10.1094/PHYTO-12-16-0435-RVW.

• “The Life Cycle of Ergot,” 15–25, 1970. https://doi.org/10.1159/000388177.