ergot.alkaloids.chem.rev, biotransformation
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RECENT INVESTIGATIONS
ON
ERGOT
ALKALOIDS’
ARTHUR STOLL
Sandoz Ltd., Bade, Switzerland
Received May
13,
1960
As
a result of the combined efforts of chemists and biologists, numerous fungi
have, in the last few years, been brought into the forefront of scientific interest.
From these low forms of life, extremely valuable therapeutic agents have been
derived. These are the so-called “antibiotics,” which are among the most power-
ful weapons available in the fight against infectious diseases. That fungi can
provide useful remedies is, however, no new discovery. The fungus
Claviceps
purpurea,
which produces the ergots seen in the ears of infected rye, has been
employed on a purely empirical basis in popular medicine for several hundred
years and has claimed the interest of
numerous research workers for many
decades.
This review will not deal in detail with the interesting history of ergot, an
excellent account of which is given in George Barger’s monograph
Ergot and
Ergotism,
published in 1931, but will start with the most recent stage
in
the
development of ergot research, that which began somewhere around the year
1920 with the isolation and preparation in
a
pure state
of
the first homogeneous
ergot alkaloid, ergotamine. The idea that the active principles of ergot are al-
kaloids only began to find general acceptance about twenty-five years ago.
Since then, the ergot alkaloids and the derivatives prepared from them syntheti-
cally have become valuable and, in some cases, indispensableremedies in the most
varied fields of medicine.
The natural alkaloids
of
ergot which have
so
far been isolated are shown in
table
1.
Their classification into three groups-the ergotamine group, the ergo-
toxine group, and the ergobasine (ergonovine) group-is based upon differences
in their chemical structure. As this table shows, the ergot alkaloids occur
in
pairs. The two alkaloids
of
a pair are stereoisomers and each readily undergoes
rearrangement to the other. This isomerism is due to the isomerism between
lysergic and isolysergic acids, the parent compounds from which all the alkaloids
of
ergot are derived. Whether existing independently or forming part of the
alkaloid molecule, lysergic acid readily undergoes rearrangement to the isomeric
isolysergic acid and
vice versa.
The natural levorotatory ergot alkaloids are de-
rived from lysergic acid, whereas the isomeric dextrorotatory members of the
pairs are derived from isolysergic acid. This isomerism is bound up with a num-
ber
of
interesting problems which will be discussed later. It is important to note
that the natural levorotatory alkaloids have a powerful pharmacological action,
whereas the corresponding dextrorotatory compounds possess only a fraction of
the activity
of
their levorotatory isomers.
Rased on
a
lecture delivered before the Organic Colloquium at, Harvard University on
May
9,
1950.
197
198
ARTHUR STOLL
Before considering the structure
of
the ergot alkaloids, attention should
be
directed to a few points in connection with the individual alkaloids listed in
table
1.
The first five pairs
of
alkaloids are presented
in
the chronological order
of their discovery. The first is the alkaloid pair ergotamine-ergotaminine. Ergot-
amine
(14)
was isolated in crystalline form and subjected to chemical analysis
as long ago as
1918.
Not long afterwards, the observation was made that it could
readily be converted into the strongly dextrorotatory but pharmacologically
less active ergotaminine.
TABLE
1
The
natural
alkaloids
of
ergot and their dextrorotatory isomers
NAME
DISCOVERER
1
1. Ergotamine group:
1
Stoll
(1918)
Ergotamine
Ergotaminine
-
155"
+385"
1
Smith and Timmis
(1936)
I
I
-
179"
+420"
Ergosine
Ergosinine
2.
Ergotosine group:
Ergocristine
Ergocristinine
-183"
+
366
'
Stoll and Burckhsrdt
(1937)
Ergokrgptine
Ergokryptinine
-187"
+108"
Stoll and Hofmann
(1943)
Ergocornine
Ergocorninine
-188"
+ago
Stoll and Hofmnnn
(1943)
I
3.
Ergobssine
group:
Ergobasine
Dudley and Moir
Kharaseh and Legnult
Stoll and Burckhardt
Thompson
(1935)
-44"
El gdiasinine
$414'
Preliminary experiments on the pharmacological properties of pure ergotamine
carried out by Stoll, together with the investigations of Spiro
(13)
and the some-
what later and more detailed studies
of
Rothlin, showed that ergotamine in
very small doses possesses the entire action of a good ergot preparation,
a
fact
which
was
confirmed by the first clinical trials.
It
was found that in obstetrics
and gynecology, the only field of application
of
ergot at that time, ergotamine
could be employed with complete satisfaction in all the indications.
It
was thus
clear that the specific active principles of ergot must be alkaloids, a fact which
was of
decisive importance for the further development
of
the chemistry and
pharmzcology of ergot. Nevertheless, until about
1925,
and in some places still
199
ERGOT
ALKSLOIDS
later, the view was prevalent that the ergot alkaloids had given disappointing
results when used clinically and that the therapeutic significance of ergot could
not, therefore, be due to its alkaloid content. The very numerous pharmacologi-
cal and clinical studies carried out with ergotamine accomplished valuable
pioneer work, yet the view which is generally accepted today, that the specific
active principles of ergot are alkaloids, only really took root after the discovery
of ergobasine (ergometrine, ergonovine) in the middle of the
1930’s.
The second pair of alkaloids in table
1,
ergosine and its isomer ergosinine, was
isolated by Smith and Timmis (12) in 1936, but neither alkaloid has yet been
introduced into medicine.
Although there are a number of peculiar features connected with the di-scov-
ery and chemical investigation of the three pairs of alkaloids comprising the
ergotoxine
group-ergocristine-ergocristinine,
ergokryptine-ergokryptinine,
and
ergocornine-ergocorninine-it is only possible in this review to give a brief ac-
count of the research. In 1906, an apparently homogeneous but amorphous
alkaloid preparation was isolated from ergot by Barger and Carr (1) in England
and simultaneously by the Swiss pharmacist Kraft
(11).
The latter investigator
designated the product “hydroergotinine,” but the name
ergotoxine
is the one
which has become universally accepted in the literature. As the result of various
chemical and pharmacological investigations and considerations, it was shown
that, although ergotoxine had in the meantime been obtained in a crystalline
form, it was nevertheless not a homogeneous substance but a mixture of three
isomorphous ergot alkaloids. One of these, ergocristine (16), had already been
isolated in 1937, while the other two were previously unknown and were named
ergokryptine and ergocornine (19).
All the alkaloids of ergot, including ergobasine, contain either lysergic acid or
isolysergic acid as the principal and characteristic constituent of the molecule.
The alkaloids of the ergotamine and ergotoxine groups are polypeptides, the
lysergic or isolysergic acid being joined to other amino acids. They thus occupy a
special place among the vegetable alkaloids.
The last pair of alkaloids shown in table
1, ergobasine-ergobasinine,
has a
simpler structure, lysergic acid
or
isolysergic acid being combined merely with
an aminoalcohol. Shortly after Jacobs (6) had established the composition of
ergobasine-which is known in England as ergometrine and in America as
ergonovine-its partial synthesis, the first to be achieved in the field of ergot
chemistry, was accomplished by Stoll and coworkers.
The investigations on the constitution of the ergot alkaloids proceeded along
two independent paths, being concerned, on the one hand, with the structure
of
the lysergic acid portion of the molecule and, on the other, with that of the basic
side chain connected wit)hit. While all the details regarding the structure of the
lysergic acid portion have now been established with certainty, the constitution
of
the peptide portion
is
still being ardently investigated.
-4
closely connected
question is that of the linkage between the peptide portion and lysergic acid,
regarding which no very definite information is yet available.
Fundamental knowledge regarding the structures of lysergic and isolysergic
acids and of the individual components of the peptide portion
is
due to the in-
200
ARTHUR STOLL
vestigations carried out by Jacobs and Craig at the Rockefeller Institute in
New York City. Thus, from cleavage products obtained by the action of ener-
getic reagents, Jacobs
(3,
9) was able, as far back as 1938, to deduce formulas
for lysergic acid and isolysergic acid which were in agreement with their reactions
and with structural considerations.
COOH
COOH
I
I1
Lysergic acid (Jacobs)
Isolysergic acid
In these formulas the following groups may be clearly recognized: an indole
system (rings
A
and B), a naphthalene system (rings
A
and
C),
and
an
N-
methylquinoline system (rings C and D). The difference between lysergic acid
and isolysergicacid was attributed by Jacobs to a difference in the position of the
double bond in ring D. This double bond is readily hydrogenated, giving rise to
corresponding dihydro acids. Since, according to the above formulation, the
dihydro acids exhibit asymmetric carbon atoms at positions
5,
8, and 10, it was
to be anticipated that saturation of the double bond with hydrogen would lead
to complicated racemic mixtures. This, in fact, proved to be the case. Bearing
in mind these complications, Uhle and Jacobs
(28)
in 1945 carried out the total
synthesis of a mixture of racemic dihydrolysergic acids and thus proved the
correctness of the
skeleton
in their formula for lysergic acid. The following scheme
illustrates the highly original synthesis employed by them
:
aoN
[I::]
Na
Bromoacetal
Cyanoacetal
CN
I
3-aminonaphthostyril
,
H
C-CH
\\
\./
CHO-
C
/
ZnClr
HCl
Ho
-+
Sodium salt
of
cyanomalondialdehyde
WN6
3-
(2-Cyano-2-formyl-
ethylideneamino)
-
naphthostyril
201
ERGOT
ALKALOIDS
CH3
-c1
HOOC
HOOC
pg
+=<
CHsI, AgCl
Ht
-+
”
3‘-~ino-5,6-benzoquinoline-
3,7-dicarboxylic acid lactam
“
Methochloride”
HOOC
HOOC
Na,
C4HoOH
Bouveault-Blanc reduction
QCH3
3
”
Dihydrolysergic
acid
3’-Amino-N-methyl-
1
,2,3,4-tetrahydro-5,6-
benzoquinoline-3,7-dicarboxylic
acid Iactam
The starting point in this synthesis was bromoacetal, which was converted by
means of potassium cyanide into cyanoacetal. This was subsequently treated
with ethyl formate and sodium to give the sodium salt of cyanomalondialde-
hyde, which Uhle and Jacobs then reacted with 3-aminonaphthostyril.
In
this
way they obtained
3-(2-cyano-2-formylethylideneamino)naphth0styril.
On
treat-
ment with zinc chloride and hydrochloric acid, this compound yielded 3’-amino-
5,6-benzoquinoline-3,7-dicarboxylic
acid lactam, which was converted into the
corresponding methochloride by means
of
methyl iodide and silver chloride. By
catalytic hydrogenation of this methochloride, Uhle and Jacobs were able to
obtain 3’-amino-N-methyl-l,
2,3,4-tetrahydro-5,6-benzoquinoline-3,7-dicarbox-
ylic acid lactam which, on treatment with sodium in boiling butanol, gave a
very small yield of racemic dihydrolysergic acid.
The totally synthetic preparation obtained in this way proved to be identical
with the product prepared by catalytic hydrogenation
of
the racemic lysergic
acid of natural origin. In both cases the product obtained was a mixture of
racemates.
After the ring system of lysergic acid and the nature and position
of
the sub-
stituents (carboxyl, methyl) had been established by Uhle and Jacobs by the
total synthesis
of
dihydrolysergic acid, there remained two further questions
of
importance regarding the fine structure of lysergic acid still to be settled:
(1)
the position of the readily reducible double bond in
ring
D and
(2)
the mecha-
nism
of
the reaction by which lysergic acid isomerizes to isolysergic acid and
vice
versa.
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