The Chemistry and Biology of Isoquinoline Alkaloids

314 Pages·1985·19 MB·English

by  N. G. Bisset (auth.)

Proceedings in Life Sciences
The Chemistry
and Biology
of Iso quinoline
Alkaloids
Edited by
1. D. Phillipson, M. F. Roberts,
and M. H. Zenk
With 178 Figures
Springer-¥erlag
Berlin Heidelberg NewY ork Tokyo
Professor Dr. J. DAVID PmLUPSON
Dr. MARGARET F. ROBERTS
Department of Pharmacognosy
The School of Pharmacy
Brunswick Square
London, WCIN lAX, United Kingdom
Professor Dr. M. H. ZENK
Pharmazeutische Biologie
Universitiit Miinchen
KarlstraBe 29
8000 Miinchen 2, FRG
ISBN-13: 978-3-642-70130-6 e-ISBN-13: 978-3-642-70128-3
DOl: 10.1007/978-3-642-70128-3
Library of Congress Cataloging in Publication Data. Main entry under title: The chemistry and biology of
isoquinoline alkaloids (proceedings in life sciences). Based on lectures presented at a symposium arranged
by the Phytochemical Society of Europe in Apr. 1984. Includes bibliographies and index. 1. Isoquinoline
Congresses. 2. Alkaloids-Congresses. 3. Botauical chemistry-Congresses. 4. Plants-Composition-Con
gresses. I. Phillipson, J.D. (John David) II. Roberts, M.F. (Margaret F.) III. Zenk, M.H., 1933-.
IV. Phytochemical Society of Europe. V. Series. QK898.I78C48 1985 581.19'242 84-23622
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© by Springer-Verlag Berlin Heidelberg 1985
Softcover reprint of the hardcover 1st edition 1985
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2131/3130-543210
Preface
Isoquinolines form one of the largest groups of plant alkaloids and they in
clude a number of valuable clinical agents such as codeine, morphine, eme
tine and tubocurarine. Research into different aspects of isoquinolines con
tinues in profusion, attracting the talents of botanists, chemists, bioche
mists, analysts, pharmacists and pharmacologists. Many of these aspects
are of an interdisciplinary nature, and in April 1984, The Phytochemical
Society of Europe arranged a 3-day symposium on The Chemistry and Bi
ology of Isoquinoline Alkaloids in order to provide a forum for scientists
of differing disciplines who are united by a common interest in this one
class of natural product. Each chapter in this volume is based on a lecture
given at this symposium. Attempts have been made to make the aims and
objectives, experimental findings and conclusions reached, intelligible to
scientists of differing backgrounds.
The introductory chapter, which is mainly based on a historical discus
sion, stresses that plants containing isoquinolines have proved to be both a
boon and a curse to mankind. The Opium Poppy, Papaver somniferum,
produces the medicinally used alkaloids morphine, codeine, noscapine and
papaverine whilst it also continues to provide drugs of abuse, particularly
morphine and its readily prepared O,O-diacetyl derivative, heroin. Numer
ous other alkaloids have been isolated from other members of the Papaver
acea, and a knowledge of their presence and distribution within the various
species has proved a useful adjunct to systematic botanical studies.
There is considerable variation in structure between the groups of iso
quinoline alkaloids, some being simple isoquinolines while others are com
plex dimers. About 50 simple isoquinolines occur in plants and they are
characteristic of some families such as the Cactaceae. In terest in these com
pounds h~s stemmed from the well-known hallucinogenic phenethylamine,
mescaline, and in one chapter, the occurrence of these simple isoquinolines
is reviewed.
The family Annonaceae comprises some 2000 species and only about
150 have been investigated for their chemical constituents. Studies during
the past decade have indicated that this family can perform biosynthetic
sequences which yield an array of isoquinolines. As examples of the more
unique types of isoquinolines, Erythrina alkaloids and the cularines form
the subjects of two separate chapters. Relatively little information exists
on the pharmacology of the cularines. There are now about 225 bisbenzyl-
VI Preface
isoquinolines in Nature and they occur mainly in species of the Berberida
ceae, Menispermaceae, Monimiaceae and Ranunculaceae. The distribution,
structure, structure determination and new alkaloids isolated in the period
1981-1983 form the basis of the chapters on bisbenzylisoquinolines.
The aporphine alkaloids form one of the largest groups of isoquino
lines and their biosynthesis has been extensively studied. However, less
is known about the catabolism of these alkaloids and this interesting to
pic is briefly covered. Differently substituted aporphines have been used
as rigid analogues of dopamine in order to investigate the nature of
dopamine receptors. Natural and synthetic aporphines have been used to
ascertain the structural requirements of dopamine agonists and antago
nists. Such studies are useful in designing new drugs for the treatment of
vascular diseases, convulsions and ulcers.
The chemistry and pharmacology of the morphinans continues to be a
subject of considerable scientific endeavour, and two chapters from
scientists at the National Institutes of Health reflect this interest. The
whole background to the synthetic approaches to the morphinans is
reviewed. In one chapter, the mode of action of different morphinans is
discussed, while the other deals with recent synthetic studies. Methods
are now available for the large scale production of the natural and the
unnatural isomers of all of the medically valuable opium derived mor
phinan derivatives.
Bridging the gap between pure synthetic chemistry and biosynthetic
studies is the area of biomimetic syntheses. The Ipecacuanha alkaloids
can be obtained from substituted dopamines and secologanin. Similar
studies have resulted in the isoquinoline analogues of the heteroyohim
nine alkaloids which have not yet been isolated as natural products.
The biosynthesis of the various isoquinolines is reviewed in two
chapters, one devoted solely to the morphinans and the other to the
other skeletal types. Attempts to produce morphinan alkaloids by plant
cell culture techniques has produced a flurry of activity in several labor
atories throughout the world. Four chapters are concerned with plant
cell culture techniques for the production of isoquinolines. A series of
enzymes which catalyse specific steps in isoquinoline alkaloid biosynthe
sis have been isolated in recent years and the stage is now set for the
isolation and characterization of the enzymes responsible for morphinan
alkaloid biosynthesis. The utilization of these enzymes for biotechnolo
gical conversions is now envisaged.
We express our sincere thanks to Hoechst (Frankfurt), Nattermann
(Cologne), Schering (Berlin) and Wacker (Munich) for their generous
financial support of the Symposium and to all speakers and chairmen of
the sessions. We are indebted to Dr. F. Fish, Dean of The School of
Pharmacy, for his permission to hold the Symposium at The School and
we are most grateful to Mrs Linda Lisgarten, librarian, and her staff for
invaluable help in the. editing of the manuscripts.
Spring 1985 J.D. Phillipson M.F. Roberts M.H. Zenk
Contents
Plan ts as a Source of Isoquinoline Alkaloids
N.C. Bisset (With 5 Figures) . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Chemotaxonomy of the Papaveraceae Alkaloids
V. Preininger (With 8 Figures) . . . . . . . . . . . . . . . . . . . . . . . . .. 23
Structure Activities and Pharmacological Properties of the
Opium Alkaloids
E. Lindner (With 7 Figures). . . . . . . . . . . . . . . . . . . . . . . . . . .. 38
The Occurrence of Simple Isoquinolines in Plants
J. Lundstrom (With 3 Figures). . . . . . . . . . . . . . . . . . . . . . . . .. 47
Erythrina Alkaloids
AH. Jackson (With 12 Figures) . . . . . . . . . . . . . . . . . . . . . . . .. 62
Annonaceae Alkaloids
A. Cave (With 22 Figures) . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 79
The Chemistry and Pharmacology of Cularine Alkaloids
L. Castedo (With 28 Figures). . . . . . . . . . . . . . . . . . . . . . . . . .. 102
Bisbenzylisoquinoline Alkaloids
P.L. Schiff, Jr. (With 5 Figures) . . . . . . . . . . . . . . . . . . . . . . . .. 126
Natural Dygradative Routes for the Aporphines
M. Shamma (With 5 Figures) . . . . . . . . . . . . . . . . . . . . . . . . . .. 142
Synthesis and Structure-Activity Relationships of Aporphines
as Dopamine Receptor Agonists and Antagonists
J.L. Neumeyer (With 8 Figures) . . . . . . . . . . . . . . . . . . . . . . . .. 146
The Chemistry and Pharmacology of Morphinan Alkaloids
A. Brossi (With 15 Figures) . . . . . . . . . . . . . . . . . . . . . . . . . . .. 171
VIII Contents
The Development of a Practical Total Synthesis of Natural and
Unnatural Codeine, Morphine and Thebaine
K.C. Rice (With 9 Figures) . . . . . . . . . . . . . . . . . . . . . . . . . . .. 191
Biomimetic and Total Synthesis of Monoterpenoid
Isoquinoline Alkaloids
R.T. Brown (With 7 Figures) . . . . . . . . . . . . . . . . . . . . . . . . . .. 204
The Biosynthesis of Isoquinoline Alkaloids
R.B. Herbert (With 14 Figures) . . . . . . . . . . . . . . . . . . . . . . . .. 213
Biosynthesis of Morphinan Alkaloids
E. Brochmann-Hanssen (With 7 Figures) 229
Enzymology of Benzylisoquinoline Alkaloid Formation
MH. Zenk (With 12 Figures). . . . . . . . . . . . . . . . . . . . . . . . . .. 240
Morphinan Alkaloids from Plant Cell Cultures
F. Constabel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 257
The Production of Isoquinoline Alkaloids by Plant Cell Cultures
M. Rueffer (With 3 Figures). . . . . . . . . . . . . . . . . . . . . . . . . . .. 265
Cytodifferentiation and Papaver Alkaloid Accumulation
T M. Kutchan, S. Ayabe, and CJ. Coscia (With 8 Figures). . . . . . .. 281
-Subject Index _ .................................. " 295
List of Contributors
You will find the address at the beginning of the respective contribution
Ayabe, S. 281 Jackson, A.H. 62
Bisset, N.G. 1 Kutchan, T.M. 281
Brochmann-Hanssen, E. 229 Lindner, E. 38
Brossi,A. 171 Lundstrom, J. 47
Brown, R.T. 204 Neumeyer, J.L. 146
Castedo, L. 102 Preininger, V. 23
Cave, A. 79 Rice, K.C. 191
Constabel, F. 257 Rueffer, M. 265
Coscia, C.J. 281 Schiff, P.L., Jr. 126
Herbert, R.B. 213 Shamma, M. 142
Zenk, M.H. 240
Plants as a Source of Isoquinoline Alkaloids
N. G. BISSET 1
1 Introduction
Mankind has long made use of plants containing isoquinoline alkaloids as active prin
ciples for medicinal and other purposes, and they have proved to be both a boon and
a curse. In the sections that follow these two aspects will be illustrated in a largely
historical discussion using Papaver somniferum, Argemone mexicana, and Curare as
examples; at the same time, some of the reasons for the continuing interest in this
field will become clear. An additional motive for such a discussion is that it is with
isoquinoline compounds that the whole field of alkaloid research may be said to have
begun. The fmal section is a more general account of the distribution of isoquinoline
alkaloids in the plant kingdom, together with an indication of their supposed signifi
cance.
2 Papaver
2.1 Early History
2.1.1 Archaeological Evidence
Poppy remains - seeds and capsules - have been recovered from neolithic sites chief
ly in western and western central Europe. Two of the finds include capsules of the
dehiscent type. The carbonized specimen from the lakeside dwelling at Robenhausen,
near Zurich in Switzerland, is of an unripe fruit, but its incomplete state precludes a
precise identification. The capsules from the Cueva de los MurcieIagos (Cave of Bats),
near Albunol in the southern province of Granada, Spain, date from the Late Neo
lithic, ca. 2500 BC, and have been identified as being of P.somniferum L. The poppy
finds from the Rhineland region, from lakeside dwellings in France, Italy and Switzer
land, and from Poland, some of which have been reported as P.setigerum (but cf.
Sect. 2.1.3), are far from the Mediterranean distribution range of that species and
may therefore have come from cultivated plants or from weeds among other culti-
1 Pharmacognosy Research Laboratories, Department of Pharmacy, Chelsea College, University
of London, Manresa Road, London SW3 6LX, United Kingdom
The Chemistry and Biology of Isoquinoline
Alkaloids, ed. by Phillipson et al.
© Springer-Verlag Berlin Heidelberg 1985
2 N. G. Bisset
vated plants (Schultze-Motel 1979). The massive fmds of seeds in Germany and
Switzerland suggest use as a food or a source of oil rather than as a medicine.
No poppy material has been detected at any neolithic site in the eastern Mediter
ranean or Near East (Krikorian 1975), and it is not until the Bronze Age that know
ledge of the poppy and its products appears in the eastern Mediterranean. Possibly the
earliest indication recognized so far is a portrayal of the plant, including capsule, at
the palace of Knossos in Crete; it may belong to the latter part of the Middle Minoan
III period, ca. 1600 BC (Merrillees 1979). Better known is the remarkable terra-cotta
figure of a goddess adorned with three scarified poppy capsules, clearly recognizable
as those of P.somnijerum, which has been recovered from a site at Gazi, west of
Heraklion, also in Crete. This figure is of the Late Minoan III period, ca. 1400-1350
BC. The circumstances of the fmd and the associated artefacts, as well as fmds else
where on the island, lead to the conclusion that during this period the use of opium
for religious, and probably also medicinal, purposes was known on the island (Kriti
kos and Papadaki 1967).
Contact between Crete and Cyprus goes back to at least the 16th century BC and
recent work in north-western Cyprus suggests that Cretan traders may have brought
the opium poppy to the island at about that time or a little earlier (Merrillees 1979).
From a study of the opium trade in the eastern Mediterranean Merrillees (1962,
1968, 1979) concludes that smalliong-neckedjuglets manufactured in Cyprus, which
in shape closely resemble a poppy capsule on its stem and which have been discov
ered in Egypt and elsewhere, were used for the transport of opium. Moreover, the
decoration on later types of juglets suggests the scarification and flow of latex on the
surface of the capsule. These imported juglets appear in Egypt as early as the first
half of the XVIIIth dynasty, ca. 1567-1320 BC. Other artefacts - faience beads,
-earrings, temple decorations - show that it was during this period that the Egyptians
became acquainted with the plant itself (Gabra 1956, Merrillees 1968). The reported
discovery in a tomb dating from the time of Tuthmosis III (ca. 1504-1450 BC) of an
unscarified capsule is further evidence (Merrillees 1968); however, its identification
appears not to be entirely free of doubt (Germer 1979). In the tomb of the royal
architect Cha, who died during the reign of Amenophis (Amenhotep) III (ca. 1417-
1379 BC), seven small alabaster vases were found, including one remarkably similar
in shape to the Cypriote juglets. One of these vases2 contained a product which ac
cording to chemical tests comprised vegetable fat together with iron and morphine -
hence opium (alkaloid extraction, and alkaloid and colour tests); pharmacological
tests also indicated the presence of the alkaloid (Muzio 1925, Schiaparelli 1927).
Later chemical studies on the contents of Cypriote juglets have implied the presence
of opium in some cases but not in others (Merrillees 1968).
2 Neither the excavation report (Schiaparelli) nor the report on the chemical and pharmacologi
cal work (Muzio) indicates which vase contained the material that was examined. Merrillees
(1962 pp. 290-291) remarks rather wistfully how tempting it is to identify the container con
cerned as the one vase which appears to be an imitation of the Cypriote juglets. It is perhaps
suggestive that it is with this particular vase that Muzio illustrated her original report. (Merril
lees presumably only saw the report as given by Schiaparelli which omitted the illustration
since he himself had a picture of it as part of his report (Schiaparelli 1927 Fig. 138, middle
juglet of the bottom row).