ALKALOID ERGOT

Kimia Bahan Alam II

ergot : sclerotium kering dari
fungi Claviceps purpurea
(Clavicipitaceae) berkembang
dalam ovarium rye (gandum
hitam), Secale cereale (Poaceae).
ergot : jamur patogen yang
tumbuh pada rumput liar, dan
mempengaruhi bunga.

7
6
8 N
9 5
10
4
11
12 2

13 N
14 H
Ergoline nucleus
Ergot dapat dipanen dengan
gandum, dan mencemari tepung
atau pakan ternak.
Konsumsi rye yang terinfeksi
ergot → mengakibatkan penyakit
ergotisme.
Tiga ciri gangguan klinis karena ergot :
Gangguan pencernaan, ex : diare,
sakit perut dan muntah.
Gangguan peredaran darah, ex :
vasokontriksi pada tangan dan kaki.
Gejala-gejala neurologi, ex ; sakit
kepala, vertigo, konvulsi, dan halusinasi.
Sklerotia ergot mengandung alkaloid
0,15-0,5 % (ada 50 alkaloid) :
Alkaloid utama :
(+)- asam lisergat
Ergometrine (ergonovin (AS)
dan ergobasine (Swiss)
(+)- asam lisergat
1) turunan amino alkohol larut
dalam air (20 % alkaloid
total)
2) turunan peptida yang tidak
larut dalam air ( 80 %
alkaloid total )
Ergometrine (ergonovin (AS)
dan ergobasine (Swiss)
merupakan amida asam lisergat
dan 2-aminopropanol
 BIOSYNTHETIC ORIGIN: Tryptophan

• Labelling experiments show

that the precursors of the
ergoline nucleus are
tryptophan, mevalonic
acid, and methionine: H O
– tryptophan provides the O
N R1
O

indole nucleus, C-4, C-5, and

7
8 CH3
N-6; N
O
N
H
6N
H
– mevalonic acid, via H OH 9
5 4
dimethylallyl pyrophosphate, is 10

the origin of C-7, -8, -9, -10;

– methionine (as 5-adenosyl- ERGOTAMINE
methionine) methylates N-6. N
H
 BIOSYNTHETIC ORIGIN

NH 2
COOH
DiMethylAlylTryptophan
DMAT

N
H
DMAT

• Several mechanisms have been proposed to

rationalize the first step in the elaboration
of ergoline, in other words the formation of
dimethylallyltryptophan (DMAT).
 BIOSYNTHETIC ORIGIN

OH
OH
CH3 CH3
NH 2 NH HN
COOH COOH H

N N N
H H H
DMAT Chanoclavine

• The next step leads to chanoclavine:

• DMAT (DiMethylAlylTryptophan)is M-methylated
and decarboxylated, the methyl group (Z) oxidized to
a hydroxy-methyl group (probably via an epoxide),
and the double bond isomerized.
 BIOSYNTHETIC ORIGIN
OH

CH3 CH3
HN N
H H

H H

N N
H H
Chanoclavine Agroclavine

• The next step is the formation of

agroclavine upon closure of the D ring.
• The hydroxymethyl group is oxidized to an aldehyde, which
reacts with the secondary amine.
 BIOSYNTHETIC ORIGIN

OH OH

CH3 CH3 CH3

HN N N
H H H

H H H

N N
N
H H
Chanoclavine H
Agroclavine
Elymoclavine

• Subsequently, a mono-oxygenase induces

the hydroxylation of the C-8 methyl group
(elymoclavine).
 BIOSYNTHETIC ORIGIN

OH H OH OR
CH3 CH3 CH3 CH3
N O N O N O N
H H H H

H H H

N N N N
H H H H
Elymoclavine Paspalic acid Lysergic acid
and ergopeptines

• A hypothesis is that peptide alkaloids are formed

from the aldehyde which arises from the
oxidation of the hydroxymethyl group of
elymoclavine, without going through an acid as an
intermediate (lysergic or paspalic acid).
 A B

Ergot Alkaloids:
TLC Analysis

S : Secale
cornutum
T3 = Ergometrine
T4 = Ergotamine
T5 = Ergocristine
S S
• SS:
– A. Toluol – EtOAc - Diethylamine (70:20:10)
– B. Toluol – Chlororform – EtOH (28,5:57:14,5)
• Detection: Van URK Reagent
– Van URK Reagent (0.2 g 4-Dimethylaminobenzaldehyde is solved in 25% HCl
adding one drop 10% FeCl3)
M. Ruhland, J.Tischler, Mycotoxin Research Vol. 24, No. 2 (2008), 73-79
 ERGOT OF RYE, Claviceps purpurea (Fries)
Tulasne
Industrial Fermentation
• The oxygenation of the culture medium must
be intense. Cell differentiation and alkaloid
production are controlled by the addition of
nutrients: a rich medium causes the formation
of abundant hyphal mycelium and no alkaloid
production.
• For many strains, it is the phosphate
concentration that conditions the passage from
the mycelium proliferation phase to the
biochemical differentiation phase. Tryptophan,
added at the beginning of the fermentation, acts
as an enzymatic inducer, and therefore it
increases the quantity of alkaloids formed.
 ERGOT OF RYE, Claviceps purpurea (Fries)
Tulasne
Industrial Fermentation
• The knowledge of how to develop Claviceps on
synthetic media is about one hundred years
old.
• The different Claviceps can be cultured at pHs
near 5.5, which are best adjusted with
ammonium salts of the acids of Krebs' cycle
(succinate, citrate).
• Frequently, the alkaloid production is dependent
on the phosphate concentration of the medium,
and for many strains, on the precise
concentrations of minerals (iron, zinc,
copper, boron) which directly influence the
productivity.
 Peptida mengandung siklik
tripeptida yang terikat pada asam
lisergat, melalui ikatan amida.

Berdasarkan sifat tiga asam amino :

1) Ergotamin
2) Ergoksin
3) Ergotoksin
Asam amino : alanin, valin,
leusin, isoleusin, fenilalanin,
prolin dan asam α-
aminobutirat.
Ergotamin : alanin,
fenilalanin dan prolin.
Hidrolissi : (+)-asam lisergat,
prolin dan fenilalanin, asan
piruvat, ammonia
Hidrolisis Ergotoxine : valin,
asam dimetilpiruvat dan
ammonia.

Hidrolisis ergoxine : asam α-

oxobutirat dan ammonia
Secara farmakologi yang
aktif : (+)-asam lisergat.
Bentuk diastereomeric dari
(+)-asam lisergat → (+)-
asam isolisergat (inaktif)
Mekanisme kerja alkaloid
ergot : berdasarkan reseptor
α-adrenergik, dopaminergik
dan serotenergik.
Ergometrine (ergonovine)
: aktivitas oksitoksik.
Bila terjadi hemoragi,
pendarahan dapat dikurangi
karena efek vasokontriksi.
Aktif diberikan secara oral.
MK : reseptor α-adrenergik.
Ergotamine: agonis α-
adrenoseptor dan reseptor 5-
HT.
Digunakan untuk migraine,
MK : dilatasi saluran darah
kranial.
Campuran “ergotoxine” :
turunan 9,10-
dihidro dihydroergotoxine
(co-dergocrine) →
campuran yang sama dari
dihydroergocornine,
dihydroergocristine dan
dihydroergocryptine (α-
dan β- dengan ratio 2:1)
Campuran “ergotoxine” :
MK menurunkan efek
vasokontriksi, dan
dihydroergotoxine : aktivitas
vasodilator serebral.
Peningkatan aliran darah :
untuk dimensia ringan,
memperbaiki fungsi mental
dan fisik.
Turunan semi sintetis
asam lisergat : stimulasi
reseptor dopamin di otak,
untuk penyakit Parkinson’s.
Bromocriptine (2-bromo-α-
ergocryptine), cabergoline ,
lisuride (lysuride) dan
pergolide.
Bromocriptine (2-bromo-α-
ergocryptine), cabergoline
: juga menghambat pelepasan
prolacin dari pituitaru,
menekan laktasi digunakan
untuk kanker mamae.
Turunan asam lisergat
(Lysergic acid
diethylamide atau LSD)
digunakan sebagai
halusinogen.
Tidak adiksi, tetapi
menyebabkan trjadinya
skizoprenia dan berbahaya
secara fisik.