ergot.alkaloid.research, biotransformation
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Progress and Prospects of Ergot Alkaloid Research
Joydeep Mukherjee,Miriam Menge
Institut für Technische Chemie,Universität Hannover,Callinstr.3,D-30167 Hannover,
Germany
E-mail: mukherjee@mbox.iftc.uni-hannover.de
Ergot alkaloids, produced by the plant parasitic fungi
Claviceps purpurea
are important
pharmaceuticals. The chemistry, biosynthesis, bioconversions, physiological controls, and
biochemistry have been extensively reviewed by earlier authors.We present here the research
done on the organic synthesis of the ergot alkaloids during the past two decades.Our aim is
to apply this knowledge to the synthesis of novel synthons and thus obtain new molecules by
directed biosynthesis.The synthesis of clavine alkaloids,lysergic acid derivatives,the use of
tryptophan as the starting material,the chemistry of 1,3,4,5-tetrahydrobenzo[
cd
]indoles,and
the structure activity relationships for ergot alkaloids have been discussed.Recent advances
in the molecular biology and enzymology of the fungus are also mentioned.Application of
oxygen vectors and mathematical modeling in the large scale production of the alkaloids are
also discussed.Finally,the review gives an overview of the use of modern analytical methods
such as capillary electrophoresis and two-dimensional fluorescence spectroscopy.
Keywords.
Ergot,Alkaloid synthesis,Claviceps,Directed biosynthesis,Bioreactors
1
Introduction
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2 Chemistry,Bioconversions,and Directed Biosynthesis
. . . . . . 2
2.1 Chemical Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.1.1 Chemical Structures . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.1.1.1 Clavine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.1.1.2 Simple Lysergic Acid Derivatives . . . . . . . . . . . . . . . . . . . 4
2.1.1.3 Ergopeptines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2.1.1.4 Ergopeptams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2.1.2 Synthesis of Clavine Alkaloids and Lysergic Acid Derivatives . . . 5
2.1.3 Use of Tryptophan as the Starting Material . . . . . . . . . . . . . 7
2.1.4 1,3,4,5-Tetrahydrobenzo[
cd
]indoles . . . . . . . . . . . . . . . . . 7
2.1.5 Structure Activity Relationships . . . . . . . . . . . . . . . . . . . 8
2.2
Bioconversions ofErgot Alkaloids . . . . . . . . . . . . . . . . . . 10
2.3
Directed Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . 10
3
Molecular Biology
. . . . . . . . . . . . . . . . . . . . . . . . . . . 12
4
Fermentation Technology
. . . . . . . . . . . . . . . . . . . . . . . 13
5
Analytical ethods
. . . . . . . . . . . . . . . . . . . . . . . . . . 16
6 Conclusions
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Advances in Biochemical Engineering/
Biotechnology,Vol.68
Managing Editor: Th.Scheper
© Springer-Verlag Berlin Heidelberg 2000
2
J.Mukherjee · M.Menge
1
Introduction
Today, ergot alkaloids have found widespread clinical use and more than 50
formulations contain natural or semisynthetic ergot alkaloids.They are used in
the treatment of uterine atonia, postpartum bleeding, migraine, orthostatic
circulatory disturbances, senile cerebral insufficiency, hypertension, hyper-
prolactinemia, acromegaly, and Parkinsonism. Recently, new therapeutic ap-
plications have emerged, e.g., against schizophrenia and for therapeutic usage
based on newly discovered antibacterial and cytostatic effects,immunomodula-
tory and hypolipemic activity.The broad physiological effects of ergot alkaloids
are based mostly on their interactions with neurotransmitter receptors on the
cells. The presence of “hidden structures’’ resembling some important neuro-
humoral mediators (e.g.,noradrenaline,serotonin,dopamine) in the molecules
of ergot alkaloids could explain their interactions with these receptors [1].
Ergot alkaloids are produced by the filamentous fungi ofthe genus,
Claviceps
(e.g.,
Claviceps purpurea
– Ergot, Mutterkorn). On the industrial scale these
alkaloids were produced mostly by parasitic cultivation (field production of the
ergot) till the end of the 1970s. Today this uneconomic method has been re-
placed by submerged fermentation. Even after a century of research on ergot
alkaloids the search still continues for new,more potent and more selective
ergot alkaloid derivatives.
A number of reviews have been published over the years.Some of the most
recent are [2–9].Much has been said about the chemistry,biosynthesis,physio-
logical controls,and biochemistry of the fungus
Claviceps purpurea
.We present
this review focusing on the organic synthesis of ergot alkaloids which has been
put aside as impracticable. Nevertheless, its importance lies in the targeted
development of new drugs, establishment of pharmacophore moieties, and
finally what we believe to be the most interesting – probing the biosynthetic
route and the development of synthons which, when added to the growing
culture of
Claviceps purpurea
, will yield new alkaloid molecules. This review
also gives information about recent progress in molecular biology, fermenta-
tion technology,and analytical methods as applied to ergot alkaloid research.
2
Chemistry,Bioconversions,and Directed Biosynthesis
There has been a continued effort towards the search for new ergot alkaloid
molecules. In this exploration various approaches have been taken. The first
approach is the total chemical synthesis of ergot alkaloids and the synthesis of
analogs thereof with improved biological properties. Due to their property of
regional selectivity with polyfunctional molecules, biological systems have
advantages over many chemical reagents which cannot distinguish between
multiple similar functional groups.Bioconversion,thus,is the second approach.
Directed biosynthesis represents the third approach in which new ergot
alkaloid molecules can be obtained by feeding the
Claviceps
with appropriate
precursors. This kind of external regulation holds promise for obtaining new
3
Progress and Prospects of Ergot Alkaloid Research
pharmacologically interesting alkaloid analogs.Our objective in this part of the
review is to unify the knowledge gained in these endeavors.
2.1
Chemical Synthesis
2.1.1
Chemical Structures
Most of the natural ergot alkaloids possess the tetracyclic ergoline ring system
as their characteristic structural feature (Fig.1).
In the majority of ergot alkaloid molecules,the ring system is methylated on
nitrogen N-6 and substituted on C-8.Most ergot alkaloids have a double bond
in position C-8, C-9 (
D
8,9
-ergolenes, C-5 and C-10 being the asymmetric cen-
ters) or in position C-9,C-10 (
D
9,10
-ergolenes,C-5 and C-8 being the asymmetric
centers).The hydrogen atom on C-5 is always in
b
-configuration.
D
8,9
-Ergolene
has the hydrogen atom at C-10 in
a
-configuration,
trans-
to 5-H. The asym-
metric carbon atom at C-8 of
D
9,10
-ergolene gives rise to two epimers,ergolenes
and isoergolenes [2,3,7,9].
The classification of the ergot alkaloids are based on the type of substituent
at C-8 and are divided into four groups:
– Clavine alkaloids
– Simple lysergic acid derivatives
–Ergopeptine alkaloids
– Ergopeptam alkaloids
2.1.1.1
Clavine Alkaloids
The clavines are hydroxy and dehydro derivatives of 6,8-dimethylergolenes and
the corresponding ergolines. This group includes the chanoclavines with an
open D-ring between N-6 and C-7.Figure 2 shows the structure of chanoclav-
ine I.This group is described in detail in a review [7].
Fig. 1.
Ergoline ring system
Fig. 2.
Chanoclavine I
4
J.Mukherjee · M.Menge
2.1.1.2
Simple Lysergic Acid Derivatives
The derivatives of lysergic acid are amides in which the amidic moiety is
formed by a small peptide or an alkylamide.The derivatives of (+)-lysergic acid
with 8
b
-configuration are pharmacologically active.Nonpeptide amides of ly-
sergic acids isolated from ergot fungi are ergometrine,lysergic acid 2-hydroxy-
ethylamide,lysergic acid amide,and paspalic acid (Fig.3).Further information
is available in [2,3,7].
a b
Fig. 3.
a
Paspalic acid.
b
Simple derivatives of lysergic acid: R=OH, lysergic acid; R=NH
2
,
lysergic acid amide; R=NHCHOHCH
3
, lysergic acid 2-hydroxyethylamide; R=NHCHCH
3
CH
2
OH,ergometrine
2.1.1.3
Ergopeptines
The ergopeptines,also called cyclol ergot alkaloids (CEA) are composed of two
parts,namely lysergic acid and a tripeptide moiety.Figure 4 shows the general
structure of the ergopeptines.
Their characteristic feature is the cyclol part which results from the reaction
of an
a
-hydroxy-amino acid adjacent to lysergic acid with a carboxyl group of
proline.Amino acid
III
of this tripeptide is l-proline and is common to all the
naturally occurring ergopeptines. Their molecular structures have been
described by the exchangeability of the l-amino acid
I
and the l-amino acid
II
between alanine, valine, phenylalanine, leucine, isoleucine, homoleucine, and
a
-aminobutyric acid. The groups of the ergopeptines formed by the com-
bination of these amino acids are ergotamine, ergotoxine, ergoxine, and
ergoannines [2,7].
Fig. 4.
General structure ofergopeptines.(R
1
=substituent ofamino acid
I
;R
2
=substituent of
amino acid
II
;amino acid
III
is l-proline)
5
Progress and Prospects of Ergot Alkaloid Research
2.1.1.4
Ergopeptams
Ergopeptams are noncyclol lactam ergot alkaloids (LEA). Their structure is
similar to ergopeptines except that the amino acid
III
is d-proline and the
tripeptide chain is a noncyclol lactam (Fig. 5). The ergopeptams are further
classified as ergotamams,ergoxams,ergotoxams,and ergoannams [2,7,9].
Fig. 5.
General structure ofergopeptams.(R
1
=substituent ofamino acid
I
;R
2
=substituent of
amino acid
II
;amino acid
III
is d-proline)
2.1.2
Synthesis of Clavine Alkaloids and Lysergic Acid Derivatives
The ergoline nucleus has long been a challenging target for total synthesis with
attempts dating back to the classic work of Uhle in 1949 and culminating in the
synthesis of lysergic acid by Kornfeld and coworkers in 1954.The central inter-
mediate in several successful syntheses,for example Ramage et al.in 1976,Nichols
et al.in 1977,and Kornfeld and Bach in 1971,has been Uhle’s ketone,either as the
protected derivative or its carbonyl transposition (for references see [10,11]).The
total synthesis of ergot alkaloids has received increasing attention in the 1980s
and 1990s,is the focus of this section,and is presented in tabular form (Table 1).
Table 1.
Overview of the research work done on the chemical synthesis of ergot alkaloids
Target
Strategy/reaction
Reference
(±)-Lysergic acid
Reductive photocyclization of the enamide,derived [12]
from a tricyclic ketone followed by ring opening
of the resulting dihydrofuran derivative
Racemic lysergene,
Reductive photocyclization of the furylenamide
[13]
agroclavine
followed by formation of the dihydrofuran ring;
final products were formed by ring opening
(±)-Elymoclavine,
Synthesis according to the synthetic route
[14]
(±)-isolysergol
involving enamide photocyclization
(±)-Isofumigaclavine B,
Reductive photocyclization of the enamide followed [15]
methyl(±)-lysergate,
by glycol formation and oxidative cleavage of the
methyl(±)-isolysergate
dihydrofuran ring
(±)-Agroclavine,
Reductive photocyclization of the enamide followed [16]
(±)-agroclavine I,
by glycol formation and oxidative cleavage of the
(±)-fumigaclavine B,
dihydrofuran ring
lysergene
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