Plants for Medicines: A Chemical and Pharmacological Survey of Plants in the Australian Region

By DJ Collins, CCJ Culvenor, JA Lamberton and 2 more

This book gives details of alkaloid and anti-tumour screening by the CSIRO of nearly 2000 species, the pharmacological testing of the alkaloids of selected species, and the chemical fractionation of those species which had reproducible tumour-inhibiting properties.

The book includes 64 colour plates and over 400 line illustrations of chemical structures.

• Language: English
• Publisher: CSIRO PUBLISHING
• Release date: Jan 1, 1990
• ISBN: 9780643102743

Book preview

A Chemical and Pharmacological Survey

of Plants in the Australian Region

Publication of this work has been supported by

Glaxo Australia Pty Ltd, Melbourne, Australia

and

DNA Pharmaceuticals, Inc., New Jersey, USA

A Chemical and Pharmacological Survey

of Plants in the Australian Region

DJ. Collins, PhD

Reader, Department of Chemistry,

Monash University

C.C.J. Culvenor, DPhil, DSc,

Chief Research Scientist,

CSIRO Division of Animal Health

J.A. Lamberton, DSc,

Formerly Chief Research Scientist,

CSIRO Division of Applied Organic Chemistry

J.W. Loder, PhD,

Principal Research Scientist,

CSIRO Division of Chemicals and Polymers

J.R. Price, KBE, D.Phil, DSc, FAA

Formerly Chief, CSIRO Division of Organic Chemistry, 1961-66

Member and Chairman of Executive, CSIRO, 1966-77

National Library of Australia

Cataloguing-in-Publication Entry

Plants for medicines: a chemical and pharmacological

survey of plants in the Australian region.

Includes bibliographies and indexes.

ISBN 0 643 04992 7.

1. Botany, Medicinal - Australia. 2. Medicinal

plants - Australia - Composition. 3. Botanical

chemistry - Australia. I. Collins, D.J,

(David John), 1931- . II. CSIRO.

581.634099

© CSIRO Australia, 1990

Front cover:

Castanospermum australe (Photo Bob Campbell)

This book is available from:

CSIRO Publications,

314 Albert Street,

East Melbourne, Victoria 3002

Australia

Telephone: [phone]

Fax: [phone]

Cover design by John Best and Franz Spranger,

CSIRO Editorial Services Section, Melbourne.

Page layout using a Macintosh II and QuarkXPress

Version 2.1.

Typeset in 10/11 point Garamond using a Varityper

VT 600 laser printer.

Chemical drawings compiled using ChemDraw 2.1.2.

Printed in Melbourne, Australia by Brown Prior Anderson Pty Ltd

ESS/PAS 1000/1990

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Contents

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Preface

1. The Phytochemical Survey and the CSIRO Screening Programme

Origin and Scope

Alkaloid Investigations

Anti-tumour Investigations

Poisonous Plants

2. Alkaloid and Anti-tumour Screening Results

Alkaloid Screening Methods

Plant Names

Pharmacological Testing and Anti-tumour Screening

Alkaloid Testing and Anti-tumour Screening Results

3. Pharmacology of Alkaloids

Test Procedures

Results

Species Tested

4. Anti-tumour Constituents

Fractionation of Active Plants

Testing of Pure Compounds

5. Colour Plates

6. Bibliography of Australian Phytochemistry, 1940-1987

7. Additional References

8. Indexes

8.1 Plant Genera with Family Correspondence

8.2 Plant Families

8.3 Authors

8.4 Chemical Structures

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Preface

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The organised investigation of the Australian flora for constituents of value as medicinal drugs or for other purposes had its origin in the Second World War (1939-1945). The need for several essential drugs of plant origin focussed attention on finding local sources and, in turn, on the paucity of phytochemical knowledge of the indigenous flora.

Investigations were initiated by Dr. C. Barnard, Division of Plant Industry, Council for Scientific and Industrial Research (CSIR, later to become the Commonwealth Scientific and Industrial Research Organisation, CSIRO), Mr. H. Finnemore, Department of Pharmacy, University of Sydney, and Professor R.D. Wright and Dr. F.H. Shaw, Department of Physiology, University of Melbourne. At the end of the war, activities were increased substantially by the appointment to CSIRO of a botanist, Dr. L.J. Webb (Division of Plant Industry) and an organic chemist, Dr. J.R. Price (Division of Industrial Chemistry).

The screening of the Australian flora for new compounds of commercial value as pharmaceuticals or veterinary and agricultural chemicals became a large CSIRO project. The novelty of the flora and the ease of obtaining new chemical compounds of interest led many chemists in Australian universities to participate in the chemical studies, some independently of the main collaborative effort which became known as the Australian Phytochemical Survey. Two important ingredients of the survey were a newsletter maintaining contacts and advising of new opportunities and availability of materials, and an undertaking by CSIRO (initially by the Division of Plant Industry, later by the Division of Industrial Chemistry) to collect botanically authenticated plant materials for all interested chemists. A series of phytochemical conferences helped maintain a sense of cooperation and common goals in what was a loosely structured collaborative programme. The pattern of activities changed with time and was greatly reduced in scale by 1975.

The chemical studies were published in the scientific literature but no general account of the Phytochemical Survey and the screening results has appeared. A committee was formed in 1984 to review the historical and scientific aspects. It decided on three objectives:

1. a historical account of the early developmental period and a summary of the principal achievements, which is to be deposited in the archives of the Australian Academy of Science;

2. publication of the main screening results (alkaloids, tumour inhibitors and the pharmacology of the alkaloids) which is the present volume;

3. a Phytochemical Data Base, to collect and make more accessible the large number of chemical publications on Australian plants. The Data Base is now in existence (contact: Dr. D. J. Collins, Department of Chemistry, Monash University).

The full bibliography and genus and author indexes of the Data Base are published here for their value in accessing Australian phytochemistry, and they also provide the main part of the references and indexes for the present work.

Structural diagrams, which have been prepared for most of the plant constituents mentioned in the text, are also separately indexed.

Some aspects of the work have been achieved only with substantial assistance from others. The revision of plant names was undertaken by staffs of the state herbaria, with particular help from Dr. R.W. Johnson and Mr. L. Pedley, Brisbane, and Dr. J. H. Ross, Melbourne. The initial preparation of the phytochemical data base depended on the cooperation of many Australian chemists and the expertise of Dr. A.D. Graddon, CSIRO Information Services Unit, Melbourne. The revision of its content and the preparation from it of the bibliography and indexes have been achieved with the valuable assistance of colleagues, Mr. L.W. Smith and Mr. L. Wursthorn. We regret that a species index to the data base has had to be left for the future.

We thank Dr. L.J. Webb for his interest and comments on botanical aspects and Professor MJ. Rand, Department of Pharmacology, University of Melbourne and Associate Professor G.A. Bentley, Department of Pharmacology, Monash University; for reading and comments on the pharmacology chapter.

For their kindness in making available photographs of plant species of phytochemical significance, we thank Dr. R.W. Johnson, Queensland Herbarium; Dr. G. Leach, Conservation Commission of the Northern Territory; Dr. T.G. Hartley, CSIRO Division of Plant Industry; Mr. J.G. Tracey, CSIRO Division of Wildlife and Ecology, Mr. S. Harris, Tasmanian Department of Lands Parks and Wildlife; Mr. L.W. Smith and especially Mr. K. Williams, Brisbane, who provided a large number of professionally taken transparencies. We are very grateful to Alecto Historical Editions, London, for permission to reproduce a selection of prints from the Banks' Florilegium, and we thank Ebes Douwma Pty. Ltd., Melbourne, for making available the negatives of the photographs of the Banks' Florilegium used to illustrate Sotheby's 1988 sale catalogue The Florilegium, Cook-Banks-Parkinson, 1768-1771.

A full account of phytochemistry in Australia remains to be told, but it is our hope that the data assembled here will add materially to the published record and assist those who continue the study of the interesting and potentially useful chemicals in our national flora.

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1

The Phytochemical Survey and the

CSIRO Screening Programme

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Origin and Scope

The investigation of the Australian flora for constituents useful as medicinal drugs or for other purposes was initiated in the early 1940s and expanded from 1945 as a prominent CSIRO project. Phytochemical studies were also taken up in several university chemistry departments. A loosely organised collaboration of chemists from CSIRO and the Universities grew out of this shared interest and became known as the Australian Phytochemical Survey. The CSIRO group provided opportunities for the exchange of information, for formal and informal meetings of participants, and supplies of botanically authenticated plant material.

The extent of the interest in plant chemistry in Australia is indicated by the appended bibliography of over 2000 papers published between 1940 and 1987 on the chemistry and related studies of Australian plant constituents. Some of these studies were carried out independently of the Phytochemical Survey, but most of the chemists involved were participants. There were extensive studies in most of the major fields of plant chemistry, ranging from alkaloids, triterpenes, diterpenes, phytoecdysteroids and long-chain compounds to flavanoids and plant phenolics. The major CSIRO interest was in alkaloid chemistry, as alkaloids were regarded as the compounds most likely to be of medicinal value. Associated programmes on stock poisons and anti-tumour plant constituents were more broadly based but, in the event, were also concerned mostly with alkaloids.

Throughout this chapter numbers in square brackets [ ] are a bibliographic reference and numbers in round brackets ( ) are references to structural diagrams.

The then CSIRO Division of Industrial Chemistry undertook the isolation of alkaloids from selected plant species, and the supply of material for pharmacological testing. The selection of plant species for investigation was facilitated by extensive spot-testing of Queensland species [1974, 1979] and a review of the medicinal and poisonous plants of Queensland [1973]. Other criteria for selecting promising species with physiological activity were their use by Aborigines as medicines or poisons, close botanical affinity with known drug sources and certain popular bush remedies, of which some were related to traditional herbals. Facilities were established for the extraction of alkaloids from plant material on the scale of 20–500 kg. A field botanist, W.T. Jones, was appointed by CSIRO to collect the species required. Verification of the large number of plant species collected was carried out mainly by the Queensland Herbarium and to a lesser extent by the National Herbarium in Victoria.

The inadequacy of the resources available for pharmacological testing led CSIRO in 1956 to enter into a collaborative agreement with the pharmaceutical company, Smith, Kline and French (SKF) of Philadelphia, under which a wide range of testing on selected alkaloids was carried out on a confidential basis by SKF. These results have not been published previously. An agreement was also made with the Cancer Chemotherapy National Service Center, NIH, Bethesda, for the screening of plant extracts and pure substances for anti-tumour activity.

In the earlier years of the alkaloid programme, attention was concentrated on the rain-forests of Queensland and northern NSW, because the early testing indicated that these regions yielded a higher proportion of alkaloid-containing species and a greater novelty of structural types. Collecting trips were made into other regions, notably Central Queensland, the tip of Cape York Peninsula, Iron Range in the lower peninsula and Fraser Island. Screening was facilitated by an improved method of field-testing [654] so that alkaloid-positive plants could be collected in quantity immediately by the screening expeditions. An independent screening of Western Australian plants was carried out by Aplin and Cannon [32], and one of the present authors (CCJC) made a screening trip through central Australia.

Screening was extended to Papua New Guinea in 1958 with the co-operation of the late J.S. Womersley, then Chief Botanist at the Department of Forests’ Herbarium at Lae. In 1963 intensive screening of the Papua New Guinea flora for alkaloids was initiated with the appointment by CSIRO of a botanist (Dr T.G. Hartley) and chemist (E.A. Dunstone). Based at the Herbarium at Lae for three years, they and their field assistants screened 2250 species for alkaloids. The plant species were identified, many at a later date, by Dr. Hartley. The results of this screening programme have been published [1078].

The phytochemical investigations most closely associated with the CSIRO screening programmes were those on alkaloids, tumour inhibitors and toxic constituents affecting livestock. Brief summaries of the scope and highlights of these studies follow.

Alkaloid Investigations

The successful production of hyoscine (1) from native Duboisia species (family Solanaceae) to meet war-time requirements provided an important stimulus to setting up the Phytochemical Survey and it is appropriate to mention it here. The presence of hyoscine and hyoscyamine (2) in D. myoporoides was known as early as 1880-90, after Bancroft, a Brisbane physician, reported that leaf extracts had atropine-like properties [c.f. 2101]. The presence of hyoscine was confirmed by Barnard and Finnemore [82, 83] and production was undertaken in 1940 by Felton, Grimwade and Duerdins Pty Ltd (later Drug Houses of Australia Ltd), Melbourne. The production of hyoscine continued on a substantial scale until the early 1950s, when it ceased [1025]. Australian production was recommenced by Chemasea Pty Ltd, Sydney, about 1968 and is continued today by Phytex Aust. Pty Ltd. A study of the alkaloids in regional populations and hybrids of D. myoporoides and D. leichhardtii in CSIRO Divison of Plant Industry in the 1940s and 1950s led to high yielding strains which have provided a basis for commercial plantations in Queensland which are a major world source of hyoscine today.

The alkaloid survey spanned a period of great changes in methods. At the beginning, classical chemical reactions and degradative methods were the main source of structural information on new alkaloids, and this was supplemented by ultraviolet absorption spectroscopy, the measurement of optical rotatory activity and total synthesis. Many new chemical reactions were discovered and derivatives became available for testing but the disadvantages were that large quantities of an alkaloid might be required and the chemical methods were very time-consuming. During the 1960s, mass and n.m.r. spectrometry became available and the ability to determine structures sometimes with only a few milligrams of material, constituted a powerful incentive for the adoption of these new spectroscopic techniques. At the conclusion of the survey activities, the structure of any suitably crystalline alkaloid, no matter how complex, could be determined by X-ray crystallography.

Certain families (Apocynaceae, Monimiaceae, Annonaceae, Lauraceae) have long been known to have a high proportion of alkaloid-positive genera and species, and many of the alkaloids from these families were expected to be the same or similar to alkaloids already known. Special interest was therefore attached to the investigation of alkaloid-positive species from plant families and genera which had not previously been found to contain alkaloid-yielding species, as these were considered to be the most likely source of new and unusual types of alkaloids. In this respect, the predominant endemic genera in Australia, Eucalyptus and Acacia, were disappointing; some simple alkaloids were found in Acacia species but none has yet been isolated from a Eucalyptus species.

hyoscine (1)

hyoscyamine (2)

melicopine (3)

During the earlier part of the programme, attention was concentrated on alkaloid-positive species of the family Rutaceae, which proved to be an abundant source of new and interesting alkaloids. Most importantly, the structures of these alkaloids could be established by the classical chemical methods and techniques then available. The first alkaloids based on the acridone ring system were found in the family Rutaceae, notably Melicope, Euodia, Acronychia and Sarcomelicope. Some of these alkaloids, for example melicopine (3), were highly substituted on one benzenoid ring and were readily converted into a series of quinonoid derivatives which were extensively studied, whereas acronycine (4) has a dimethylpyran ring. Pentaceras australis (family Rutaceae) was the source of the first alkaloids of the canthinone group which included the sulphur-containing alkaloid 4-methylthiocanthinone (5). The genera Melicope, Euodia, Acronychia (of which the species known then as A. baueri is now placed in the genus Sarcomelicope), Geijera, Lunasia and particularly Flindersia, afforded many new and interesting variants of the furoquinoline alkaloids, a few examples of which were already known. These range from examples which have few or many alkoxyl substituents eg. acronycidine (6) or have isopentenyl groups attached in various ways. Halfordia scleroxyla F. Muell. contained halfordine (7), an alkaloid of a different type.

The demonstration of the widespread occurrence of alkaloids of the furoquinoline and acridone types within the Rutaceae, and the possibility that they are useful taxonomic indicators, have been a stimulus to further studies overseas, and very large numbers of these alkaloids are now known. Metabolites related to the acridone alkaloids have been found to be accumulated in callus cultures of Ruta graveolens co-cultured with species of fungi, suggesting that some acridone compounds are phytoalexins in species of Rutaceae [2102, 2103].

The structure of the vesicant alkaloid crypto-pleurine (8) from Cryptocarya pleurosperma C. White & Francis was established by X-ray crystallography as a phenanthroindolizidine derivative, quite unlike other known alkaloids of the Lauraceae. Cryptopleurine is a very potent fungicide, but it is of limited practical use because of its highly vesicant action on human skin. The specific inhibition of protein biosynthesis shown by cryptopleurine (page 152) has found some application in biological studies. Cryptopleurine was isolated again much later from Boehmeria platyphylla Don., an unrelated plant of the family Urticaceae. B.platyphylla Don. and the related B. cylindrica Sw. were found to contain as well as cryptopleurine the biosynthetic precursors of cryptopleurine, including the new seco-base (9). The presence of cryptopleurine explained the cytotoxic and antimicrobial properties which had been observed in extracts of B. cylindrica (page 163).

acronycine (4)

4-methylthiocanthinone (5)

acronycidine (6)

halfordine (7)

cryptopleurine (8)

seco-base cf. cryptopleurine (9)

The Boehmeria alkaloids were the first isolated from plants of the Urticaceae. Another member of the family, the New Guinea species Cypholophus friesianus (K. Schum.) H. Winkler gave alkaloids of a different type. Cypholophine (10) and O-acetyl-cypholophine were shown to be imidazole alkaloids of a previously unknown type, and the structures assigned from spectroscopic data were confirmed by synthesis.

The indole alkaloids are the most extensive of all groups of alkaloids and many were isolated during the survey. Simple tryptophan derived bases were isolated from Acacia, Pultenaea, Aotus and other genera, and the relatively simple indole (11) was isolated in partially racemic form from Dracontomelon mangiferum Bl. This alkaloid is of interest as the first to be obtained within the family Anacardiaceae. 1,5-Dimethoxy-3-(dimethyl-aminomethyl)indole (12) was isolated from a Gymnacranthera species (family Myristicaceae). Other simpler indoles are the Pentaceras canthinone bases (already mentioned), but most alkaloids of this type are more complex and contain a rearranged terpenoid moiety. Complex Kopsia alkaloids were studied at an early stage of the survey, as also were Alstonia alkaloids when it was found that Alstonia constricta F. Muell. was a source of reserpine (13), although not in commercially useful amounts. In later studies of Alstonia constricta, vincamajine (14) and 17-O-(3,4,5-trimethoxycinnamoyl)vincamajine (15) were isolated for the first time from an Alstonia sp., the new alkaloid alstonilidine (16) was obtained, and the structure of the previously isolated alstonidine was shown to be (17). Neisosperma poweri (Bailey) Fosberg & Sachet [Ochrosiapoweri Bailey] (family Apocynaceae) also contained reserpine and many other alkaloids, including reserpiline (18), isoreserpiline (19), and two new bases of yohimbinoid type, namely poweridine (20) and powerine which was shown by X-ray crystallography to be 10-hydroxy-17-epi-α-yohimbine (21). From the tropical lianas, Uncaria bernaysii F. Muell. and Uncaria ferrea DC. (family Rubiaceae), the four isomeric oxindole bases, uncarines C, D, E, and F, general formula (22), were obtained. The complete stereochemistry of these bases was elucidated by n.m.r. spectroscopy and established by interconversion of the bases and by their partial synthesis from tetrahydroalstonine (23). This work for the first time clarified the relationship between isomeric oxindole alkaloids and allowed correction of the previously accepted structure of uncarine B (formosanine) (24).

cypholophine (10)

l,2,3,4,6,7-hexahydro-12H-indolo-[2,3a]quinolizine (11)

l,5-dimethoxy-3-(dimethyl-aminomethyl)indole (12)

reserpine (13)

vincamajine (14)

17-O-(3,4,5-trimethoxycinnamoyl)vincamajine (15)

The major alkaloid, antirhine, from Antirhea putaminosa (F. Muell.) Bailey was shown to be (25), and its structure was established by conversion of the dihydro derivative into the same quaternary base (26) as is obtained from dihydrocorynantheol, thereby establishing the absolute configuration of antirhine.

The most intriguing indole structures are those of the alkaloids ervatamine (27) and 20-epiervatamine isolated from Eruatamia orientalis (R.Br.) Turr. These alkaloids have attracted much attention because of their biosynthetic significance and relationship to other indole bases. Numerous other complex indoles were isolated; many were identified with alkaloids already known, e.g. 9-hydroxy-19,20-dihydrocorynantheine (gambirine) (28) from Neonauclea schlechteri (Val.) Merr. & Perry, and others such as the Elaeocarpus indoles are discussed in other sections.

alstonilidine (16)

alstonidine (17)

reserpiline (elliptamine) (18)

isoreserpiline (19)

poweridine (20)

10-hydroxy-17-epi-α-yohimbine (21)

uncarines C,D,E, and F (22)

tetrahydroalstonine (23)

uncarine B (formosanine) (24)

antirhine (25)

quaternary base from dihydroantirhine (26)

ervatamine (27)

The indole alkaloid hodgkinsine from Hodgkinsonia frutescens C.White. (family Rubiaceae) is of a different type and was shown by X-ray crystallography to be (29), which has three linked tryptamine units. A remarkable alkaloid, C55H62N10, from Psychotria beccarioides Wernh. of Papua New Guinea is even more complex and has five such tryptamine units similarly joined. Its stereochemistry has not yet been determined.

One of the major successes of the alkaloid programme was the discovery of a large group of very complex alkaloids in Galbulimima belgraveana (F. Muell.) Sprague [G. baccata Bailey, Himantandra baccata], investigated at the University of Sydney. The species is variable, material from different areas of north Queensland yielding different alkaloids. Structural investigations were helped by X-ray crystal structure determinations on himbacine and himbosine, and as a result of extensive studies the structures of all these alkaloids were established. Three structural types are represented by himbacine (30), himbosine (31) and himbadine (32).

The alkaloids from the flowers of the Tasmanian mountain plant, Bellendena montana R.Br., were the first to be reported from the large family Proteaceae. The structure of bellendine (33) has been established, and several pyrrolidine alkaloids have been isolated from two Queensland Darlingia species, also family Proteaceae. The alkaloid (34) is representative of the Darlingia bases.

Prior to this programme, the family Elaeocarpaceae was not known to contain alkaloids; now it must be regarded as one of the major alkaloid-containing families on the basis of the number of alkaloids isolated and the number of new and interesting types. Elaeocarpus species from Papua New Guinea have yielded numerous indolizidine alkaloids which range from the simpler types such as elaeokanine C (35) in E. kaniensis Schltr. to the more complex alkaloids such as (-)-isoelaeocarpiline (36) in E. sphaericus (Gaertn.) K. Schum., and the aromatic bases such as (±)-elaeocarpine (37) which predominate in E.polydactylus Schltc. The indoloindolizine elaeocarpidine (38) is the major alkaloid of E. densiflorus Knuth and a minor constituent of other species. The Elaeocarpus alkaloids have attracted much attention overseas as targets for synthetic studies, and as many as ten syntheses of the less complex alkaloids have been published.

9-hydroxy-19,20-dihydrocorynantheine (gambirine) (28)

hodgkinsine (29)

himbacine (30)

himbosine (31)

himbadine (32)

bellendine (33)

Darlingia base (34)

The Australian species Peripentadenia mearsii (C. White) L.S. Smith yielded alkaloids biosyntheti-cally linked to the Elaeocarpus indolizidine alkaloids. The major alkaloid was the pyrrolidine derivative, peripentadenine (39), and a minor alkaloid anhydroperipentamine (40). An unusual isoquinuclidine alkaloid (41) was also present.

The investigation of Aristotelia alkaloids, the other major group from the family Elaeocarpaceae, has extended to species from the New Zealand and South American flora. The Tasmanian species Aristotelia peduncularis (Labill.) Hook.f. afforded the alkaloids peduncularine (42), isopeduncularine (43), aristoteline (44), aristoserratine (45), sorelline (46), tasmanine (47) and hobartine (48). The Aristotelia alkaloids are derived from a tryptamine and a terpenoid unit, but are distinctly different from the ‘normal’ complex indole alkaloids.

elaeokanine C (35)

isoelaeocarpiline (36)

elaeocarpine (37)

elaeocarpidine (38)

peripentadenine (39)

anhydroperipentamine (40)

isoquinuclidine from Peripentadenia (41)

peduncularine (42)

isopeduncularine (43)

aristoteline (44)

aristoserratine (45)

sorelline (46)

Eupomatia laurina R.Br, belongs in the monogeneric family Eupomatiaceae, regarded as a very old, isolated family with no surviving relatives. In addition to two aporphinoid alkaloids, liriodenine (49) and norushinsunine (50), three new alkaloids were isolated. Eupolauridine was shown by synthesis to be 1,6-diazafluoranthene (51). The other two alkaloids were not structurally related. Eupolauramine was shown by X-ray crystallography to be (52) and hydroxyeupolauramine to be (53).

Within the family Liliaceae, two Queensland species yielded important new alkaloids. In Tripladenia cunninghamii D.Don [Kreysigia multiflora Reichb.] new groups of homoaporphines and homomorphines, e.g. (–)-floramultine (54) and (+)-kreysiginine (55), were found. These alkaloids are analogous to known aporphine and morphine group alkaloids found in other plant species, but they differ by having one six-membered ring expanded to a seven-membered ring. This difference arises because they are derived from the precursor phenylethyltetrahydroisoquinoline which in other species of Liliaceae (eg. Colchicum) is converted into the well-known alkaloid colchicine (56), whereas the normal aporphine and morphine alkaloids are derived from phenylmethyltetrahy-droisoquinoline. The closely related species Kuntheria pedunculata [Schelhammera pedunculata F. Muell.], afforded a large number of alkaloids, all of which have the ‘homoerythrina’ skeleton exemplified by schelhammerine (57), and they are analogous to the Erythrina alkaloids except that one ring is seven-membered, as they too are derived from phenylethyltetrahydroisoquinoline. Since their isolation from Schelhammera species, the ‘homoerythrina’ alkaloids and closely related alkaloids have been found in other plant genera which are widely separated botanically. They have been found in the genera Phelline (Aquifoliaceae), Cephalotaxus (Cephalotaxaceae), Dysoxylum (Meliaceae), and in Tasmanian Arthrotaxis species (family Taxodiaceae).

tasmanine (47)

hobartine (48)

liriodenine (49)

norushinsunine (50)

1,6-diazafluoranthene (51)

eupolauramine (52)

hydroxyeupolauramine (53)

(–)-floramultine (54)

(+)-kreysiginine (55)

Genera of the family Euphorbiaceae which had not previously been shown to contain alkaloids were particularly rewarding as a source of new types. Glochidine (58) and glochidicine (59) from a New Guinean Glochidion species, G.philippicum (Cav.) Rob., represent entirely new ring systems, respectively pyridoimidazole and pyrimidinoimidazole types. Also within the family Euphorbiaceae, the species Alcbornea rugosa (Lour.) Muell. Arg .[A. javanensis (Bl.) Muell. Arg.] contained both new guanidine alkaloids, such as the tri-isopentenylguanidine (60) and new bases such as alchornine (61) which have a hexahy-droimidazopyrimidine skeleton. Euphorbia atoto Forster contains the relatively simple alkaloid 9-aza-l-methylbicyclo[3.3.l]nonan-3-one (62) which was of interest because it is related to adaline (63), the toxic defence substance of the coccinellid insect (ladybird), Adalia bipunctata L. [2104]. Later, a substance identical with the Euphorbia atoto base was isolated from an Australian ladybird [373].

colchicine (56)

schelhammerine (57)

glochidine (58)

glochidicine (59)

tri-isopentenylguanidine (60)

alchornine (61)

9-aza-1-methylbicyclo-[3.3.1]nonan-3-one (62)

adaline (63)

porantherine (64)

Another member of the Euphorbiaceae, Poranthera corymbosa Brongn., gave some highly unusual alkaloids which included porantherine (64), porantheridine (65), O-acetylporanthericine (66), and a number of other alkaloids which have an azaphenalene skeleton, as well as a biosynthetically related quinolizidine, porantherilidine (67). The numerous synthetic studies on Poranthera alkaloids overseas have included an elegant synthesis of porantherine by E.J. Corey.

The genus Anopterus has only two species, both endemic to Australia, and belongs to the Grossulariaceae which has not previously been recorded as containing alkaloids. Both Anopterus macleayanus F. Muell. and A. glandulosus Labill. contain anopterine (68) and closely related alkaloids, all of which have an unusual variation of the ent-kaurene diterpenoid skeleton. This ring system is, so far, unique to the Anopterus alkaloids, one of the less complex of which is represented by anopterimine (69), and a more highly substituted example is (70). Oxidation of anopteryl alcohol with potassium ferricyanide gives a product with the remarkable cage structure (71).

The Planchonella species of Papua New Guinea belong to the Sapotaceae, another family not known previously to have alkaloid yielding members. Two of those examined contained pyrrolizidine alkaloids, most notably the methylthioacrylate ester (72). Within the Rhizophoraceae, the species Carallia brachiata (Lour.) Merr. contained the known alkaloid hygroline (73), and Bruguiera sexangula (Lour.) Poir. a tropane alkaloid (74) with an unusual S-containing acid, 1,2-dithiolane-3-carboxylic acid, as the esterifying acid. Two Mackinlaya species, M. macrosciadia (F. Muell.) F. Muell. from Queensland and M. sp. cf. klossii from Papua New Guinea, contained large quantities of quinazolines, eg. (75), which had already been synthesised but were not previously known as alkaloids. A minor Mackinlaya alkaloid (76) has an unusual macrocyclic ring system. These alkaloids are the first to be found in the family Araliaceae. Within the previously unexplored family Oleaceae, several Jasminum species and an Olea species were found to contain relatively simple pyridine alkaloids, for example jasminine (77).

porantheridine (65)

O-acetylporanthericine (66)

porantherilidine (67)

anopterine (68)

anopterimine (69)

unnamed Anopterus base (70)

oxidation product of anopteryl alcohol (71)

methylthioacrylate ester of laburnine (72)

hygroline (73)

Studies of Ficus species (family Moraceae) led to the isolation from F. septica of the phenanthroindolizidine alkaloids, (–)-tylophorine (78) and (+)-tylocrebrine (enantiomer of 79), and the related base (–)-septicine (80), while F. pantoniana King was the source of the first known flavanoidal alkaloids, ficine (81) and isoficine (82).

From the plant families Lauraceae and Annonaceae in particular, as well as from other sources, large numbers of aporphine and benzylisoquinoline