Dihydroergotoxine has a clinical use for patients with cerebral and peripheral
circulatory disturbances. Bromokryptine and pergolide have been used in
the therapy of Parkinson’s disease, acromegaly, and hyperprolactinemia.
Cianergoline is a potent antihypertensive. Since these ergot-related compounds
sometimes show undesirable side effects, a series of ergolines were synthesized
[53], hoping to find compounds with potent antihypertensive or dopaminergic
activity and with weaker side effects. Different (5R,8R,10R)-6-alkyl-8-ergoline
tosylates were prepared and treated with various five-membered heterocycles
containing nitrogen atoms to yield new ergolines. It was found that
(5R,8R,10R)-8-(1,2,4-triazol-1-ylmethyl)-6-methylergoline exhibited potent
dopaminergic activity, about 18-fold greater than bromokryptine mesylate.
Extremely potent dopaminergic activity was shown by (5R,8R,10R)-8-(1,2,4triazol-1-ylmethyl)-6-propylergoline, being about 220 and 1.15 times more
active than bromokryptine and pergolide mesylate, respectively. In continuation of this work, a series of (5R,8S,10R)-ergoline derivatives were synthesized [54], following the same synthetic methodology. (5R,8S,10R)-8-(1Imidazolylmethyl)-6-methylergoline and (5R,8S,10R)-2-bromo-6-methyl-8-(1,2,4triazol-1-ylmethyl)ergoline exhibited potent antihypertensive activity but without potent dopaminergic activity.
In an attempt to gain insight into the pharmacophore moiety of the ergot
alkaloids, aza-transposed ergolines were synthesized [55] with the nitrogen
atom in the 9-position by alkylation-amination of a tricyclic enamine in the
presence of ethyl a,a,-bis(dibromomethyl)acetate, triethylamine, and methylamine which led to the construction of the azatransposed ergoline.
Syntheses of potent 5-HT agonists were accomplished in several steps from a
6-iodo partial ergoline alkaloid. A new and general methodology critical for the
construction of oxazole-containing alkaloids was developed for the synthesis of
the 5-HT agonists using a novel palladium(0)- and copper(I)-cocatalyzed
cyanation reaction [56].
A new semisynthetic peptide alkaloid, 9,10-a-dihydro-12¢-hydroxy-2¢isopropyl-5¢a-(R-1-methylpropyl)ergotaman-3¢,6¢,18-trione (DCN 203–922),
which contains the unnatural amino acid l-allo-isoleucine, was prepared and
was found to have affinity to different monoamine binding sites in the brain
[57].
Because the activities of ergot alkaloids are mediated by neurotransmitter
receptors, clavine alkaloids also possess antibiotic and cytostatic activities [58,
59]. With the idea that the antineoplastic and antiviral activity of various
heterocycles can be enhanced by their N-ribosylation, N-b-ribosides of agroclavine, elymoclavine, lysergene, lysergol, and 9,10-dihydrolysergol were
prepared by SnCl 4 catalyzed ribosylation of their trimethylsilyl (TMS) derivatives with 1-O-acetyl-2,3,5-tri-O-benzoyl-b-d-ribofuranose. None of the new
compounds exhibited activity against HIV or other viruses tested [60]. N-2deoxy-d-Ribosides of agroclavine, lysergol, and 9,10-dihydrolysergol were
prepared by SnCl 4 catalyzed glycosylation of their TMS derivatives with
1-chloro-3,5-di-O-toluoyl-2-deoxy-d-ribofuranose. None of the compounds,
however, possessed antiviral activity against HIV [61].
Progress and Prospects of Ergot Alkaloid Research
9
circulatory disturbances. Bromokryptine and pergolide have been used in
the therapy of Parkinson’s disease, acromegaly, and hyperprolactinemia.
Cianergoline is a potent antihypertensive. Since these ergot-related compounds
sometimes show undesirable side effects, a series of ergolines were synthesized
[53], hoping to find compounds with potent antihypertensive or dopaminergic
activity and with weaker side effects. Different (5R,8R,10R)-6-alkyl-8-ergoline
tosylates were prepared and treated with various five-membered heterocycles
containing nitrogen atoms to yield new ergolines. It was found that
(5R,8R,10R)-8-(1,2,4-triazol-1-ylmethyl)-6-methylergoline exhibited potent
dopaminergic activity, about 18-fold greater than bromokryptine mesylate.
Extremely potent dopaminergic activity was shown by (5R,8R,10R)-8-(1,2,4triazol-1-ylmethyl)-6-propylergoline, being about 220 and 1.15 times more
active than bromokryptine and pergolide mesylate, respectively. In continuation of this work, a series of (5R,8S,10R)-ergoline derivatives were synthesized [54], following the same synthetic methodology. (5R,8S,10R)-8-(1Imidazolylmethyl)-6-methylergoline and (5R,8S,10R)-2-bromo-6-methyl-8-(1,2,4triazol-1-ylmethyl)ergoline exhibited potent antihypertensive activity but without potent dopaminergic activity.
In an attempt to gain insight into the pharmacophore moiety of the ergot
alkaloids, aza-transposed ergolines were synthesized [55] with the nitrogen
atom in the 9-position by alkylation-amination of a tricyclic enamine in the
presence of ethyl a,a,-bis(dibromomethyl)acetate, triethylamine, and methylamine which led to the construction of the azatransposed ergoline.
Syntheses of potent 5-HT agonists were accomplished in several steps from a
6-iodo partial ergoline alkaloid. A new and general methodology critical for the
construction of oxazole-containing alkaloids was developed for the synthesis of
the 5-HT agonists using a novel palladium(0)- and copper(I)-cocatalyzed
cyanation reaction [56].
A new semisynthetic peptide alkaloid, 9,10-a-dihydro-12¢-hydroxy-2¢isopropyl-5¢a-(R-1-methylpropyl)ergotaman-3¢,6¢,18-trione (DCN 203–922),
which contains the unnatural amino acid l-allo-isoleucine, was prepared and
was found to have affinity to different monoamine binding sites in the brain
[57].
Because the activities of ergot alkaloids are mediated by neurotransmitter
receptors, clavine alkaloids also possess antibiotic and cytostatic activities [58,
59]. With the idea that the antineoplastic and antiviral activity of various
heterocycles can be enhanced by their N-ribosylation, N-b-ribosides of agroclavine, elymoclavine, lysergene, lysergol, and 9,10-dihydrolysergol were
prepared by SnCl 4 catalyzed ribosylation of their trimethylsilyl (TMS) derivatives with 1-O-acetyl-2,3,5-tri-O-benzoyl-b-d-ribofuranose. None of the new
compounds exhibited activity against HIV or other viruses tested [60]. N-2deoxy-d-Ribosides of agroclavine, lysergol, and 9,10-dihydrolysergol were
prepared by SnCl 4 catalyzed glycosylation of their TMS derivatives with
1-chloro-3,5-di-O-toluoyl-2-deoxy-d-ribofuranose. None of the compounds,
however, possessed antiviral activity against HIV [61].
Progress and Prospects of Ergot Alkaloid Research
9