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, hyperprolactinemia, acromegaly, and Parkinsonism. Recently, new therapeutic applications have emerged, e.g., against schizophrenia and for therapeutic usage
based on newly discovered antibacterial and cytostatic effects, immunomodulatory 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 neurohumoral 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 of the 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 Today this uneconomic method has been replaced by submerged fermentation.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, physiological 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, fermentation 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
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, hyperprolactinemia, acromegaly, and Parkinsonism. Recently, new therapeutic applications have emerged, e.g., against schizophrenia and for therapeutic usage
based on newly discovered antibacterial and cytostatic effects, immunomodulatory 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 neurohumoral 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 of the 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 replaced 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, physiological 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, fermentation 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