Global phytochemistry: indigenous medicinal chemistry on track in southern Africa

Global phytochemistry: indigenous medicinal chemistry on track in southern Africa

Phytochemistry 65 (2004) 769–782 www.elsevier.com/locate/phytochem Editorial comment Global phytochemistry: indigenous medicinal chemistry on track ...

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Phytochemistry 65 (2004) 769–782 www.elsevier.com/locate/phytochem

Editorial comment

Global phytochemistry: indigenous medicinal chemistry on track in southern Africa

1. Introduction Southern Africa is one of the richest centers of plant diversity in the world. The flora is not only extremely rich and diverse (about 24 300 higher plant taxa) (Arnold and de Wet 1993), but is also largely endemic in character. The Cape Floristic Region with nearly 6000 endemic species is one of the world’s richest floral regions. Southern Africa has a great range of climatic zones (sub-tropical to Mediterranean) and habitat types (Afro-alpine grasslands to coastal deserts), and a correspondingly diverse and well-adapted flora. The indigenous people of southern Africa have a long history of traditional plant usage for medicinal purposes, with ca. 4000 taxa so employed. The trade in medicinal plants is an important part of the regional economy with over 700 plant species being reported as traded (Mander, 1998). In South Africa it is estimated that there are 27 million indigenous medicine consumers. Accordingly demand has exceeded sustainable supply with several species such as Warburgia salutaris (Bertol. F), Chiov. (Pepperbark Tree) and Siphonochilus aethiopicus (Schweinf.) B.L. Burtt (Wild Ginger) becoming locally extinct, especially outside of protected areas (Mander, 1998). The value of trade in ethnomedicinal plants in KwaZulu-Natal alone was estimated to be worth R60 million ($10 million) in 1998. Most households spend between 4 and 8% of their annual income on traditional medicinal services. In addition, in KwaZulu-Natal between 20 000 and 30 000 people derive an income from trading indigenous plants. Most of these are rural black women, the most marginalized group in South African society. Mander (1998) estimated that in 1998 the trade in medicinal plants in South Africa was nearly 20 000 t with a total value of $110 million. Apart from traditional plant usage, plants such as Aspalathus linearis (Burm. F) Dahlg. (Rooibos), Harpagophytum procumbens (Burch.) DC. Ex Meissn. (Devil’s Claw), Hypoxis hemerocallidea Fisch.& C.A. Mey (African potato) and Cape aloe (Aloe ferox mainly) are exported to the East and Europe. 0031-9422/$ - see front matter # 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.phytochem.2004.01.014

In this review the attempts to unravel the complex chemistry of the flora of southern Africa will be described. The task was carried out by natural products chemists from all over the world and spans the period 1900–2003. During this period decisive political and other events took place in the region, including the Anglo-Boer War, the second World War, and the arrival of Democratic Government in South Africa. All of these influenced the progress of Science in the subcontinent.

2. Early history (1900–1944) 2.1. Gold and stock diseases By 1902, the bitter Anglo-Boer War (1899–1902) in which Brit fought against Afrikaner on the southern tip of Africa, had ended. In 1910, the Union of South Africa was founded with four constituent provinces: Cape of Good Hope, Transvaal, Natal and Orange Free State. The discovery of rich gold deposits in 1884 on the Witwatersrand brought an influx of foreigners to the country, and, with it, a new and vigorous industry. However, in rural South Africa farming remained as an important mainstay of the economy. In particular, it was stock farming (cattle, sheep, goats) which had a profound influence on natural products research. Cattle, sheep, horses and donkeys were dying in great numbers from diseases such as ‘‘slangkop’’ poisoning (Homeria pallida, Rindl, 1924), ‘‘stywe’’ siekte (liver damage and stiffness) caused by Crotolaria burkeana, (Theiler, 1911), ‘‘vermeersiekte’’ (see below), ‘‘geel dikkop’’ (see below) and ‘‘gifblaar’’ poisoning (fluoroacetate poisoning from the plant Dichapetalum cymosum, see below). All of these fatal diseases came about as a result of stock grazing on a variety of poisonous plants. As an example of the seriousness of the problem, it is estimated that in the years 1926–1927 some 600 000 sheep died in the North-Western Cape as a result of the ‘‘geel dikkop’’ disease. Ingestion of the plant Tribulus terrestris (devil’s thorn), coupled with exposure of the animal to strong sunlight, leads to a phytotoxic disease,

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now known as tribulosis which causes almost certain death of the animal. The plant Geigera aspera (Asteraceae) grows in open grassland and causes ‘‘vermeersiekte’’ (vomiting disease), characterized by an initial lameness in the animal followed by severe vomiting, asphyxia and death. In the years 1929–1930 a million sheep died from this disease in the Karroo regions of the Cape (Vahrmeyer, 1982). Despite the brave efforts by Hutcheon (1902) and Rimington and Roets (1936), the structure of the active

principle, geigerin (1) was only established in 1957 by Perold, working at the National Chemical Laboratory, Pretoria (Perold, 1957) and Barton (Barton and Levisalles, 1958). In Perold’s proposal only the position of a secondary hydroxyl group was out of place (2). A plant occurring mainly in Natal and the Orange Free State was Urginea macrocentra, commonly referred to as ‘‘Natal slangkop’’. Ingestion of the bulb by cattle leads to respiratory problems, muscular tremors and finally death. Preliminary structural work on the active

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principle by the first researcher in this area (Juritz, 1923) attracted world-wide attention. It was, however, not until 1949 that Louw was able to establish the structure of the toxic principle, the cardiac glycoside, named transvaalin (3) (Louw, 1949). Subsequently, Tamm (1953), in Switzerland, was able to show that transvaalin and scillaren A were identical.

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It is important to note that almost all the work on toxic plants in the period under discussion emanated from the Chemistry Laboratory of the Onderstepoort Veterinary Research Institute outside Pretoria. This institute achieved world acclaim for its toxicological and chemical work particularly under the leadership of Sir Arnold Theiler and Professor P.J. du Toit (Theiler et al., 1923).

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One of the most important events and one which focused the attention of the international community on Onderstepoort occurred in late 1944, when Dr. J.S.C. Marais isolated monofluoroacetic acid (FCH2COOH) (LD50=0.25–0.5 mg/kg sheep) from the plant Dichapetalum cymosum (gifblaar/poison leaf) (Marais, 1944).

This was the first recorded instance of fluorine occurring in a natural product. Since its discovery fluoroacetic acid has been found in other plants and its mode of action, leading to death of the host, has elicited a research area in its own right. In 1982, when the 13th International Symposium on Natural Products Chem-

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istry was held in South Africa Marais’ achievement, some 40 years earlier, was highlighted by using the ‘‘gifblaar’’ plant as an emblem on the outside cover of the official conference programme. Two other factors which served to stimulate the interest in the chemistry of southern African natural products in the middle 1930s were the appearance of the book on the ‘‘Toxicology of plants in South Africa’’ (1934), by Professor Douw G. Steyn (also from Onderstepoort) and the large treatise by Watt and BreyerBrandwijk. The latter book was revised and republished in 1962 and has been the ‘‘bible’’ of natural product chemists in Southern Africa for the past 70 years. Its contribution to the development of natural products chemistry in southern Africa is immeasurable.

3. The period 1945–1983 3.1. A changing world and a change in the face of chemistry The Second World War had ended in 1945 and this in itself changed the face of South and southern Africa. Science research received a tremendous boost through the establishment in 1945 of the Council for Scientific and Industrial Research (CSIR), based in Pretoria. Its founding president was Sir Basil Schonland who later

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became Director of the Atomic Energy Research Establishment in Harwell. Further changes which had a profound influence on Natural Products research were: 1. The emergence of natural products research groups at South African universities assisted by reasonable financial support for expensive instrumentation by Government. Leading this group was Professor Frank Warren (ex Imperial College) at the University of Natal in Pietermaritzburg (see below). Other successful plant chemistry groups came into being at Pretoria University under Professor H.L. de Waal (plant alkaloids, 1951), Professor Dawie Roux at Rhodes University (naturally occurring tannins and subsequent development of phenolic wood glues for the chipboard industry, 1967), Professor Alistair Stephen in Cape Town (1972, carbohydrates of indigenous Acacias), Professor Douglas Rivett (Rhodes University) (1975, variety of natural products with emphasis on the Lamiaceae), Professor D.A.H. Taylor (ex Oxford and Ibadan, Nigeria) in Durban (1984, complex limonoids from the Meliaceae), Professor C. van der Merwe Brink in Bloemfontein (1970, pterocarpans and other fish poisons), Professor Guido Perold in Johannesburg at the University

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of the Witwatersrand (1972), (elegant structural elucidation of compounds from the Proteaceae). This time round Perold was not dealing with stock poisons but with compounds which were shown to be valid taxonomic indicators of the genus Leucospernum and Leucodendron (Proteaceae). The compound conocarpin (5) is one such compound. 2. The establishment by the Government of the National Chemical Research Laboratory (NCRL), together with other related institutes, on a 200 ha area of land on the outskirts of Pretoria, in 1946. The laboratory provided a national facility for sophisticated analytical instrumentation including one of the first 500 MHz NMR instruments. It attracted a crop of outstanding natural products chemists such as Drs. P. Enslin, P.S. Steyn, R. Vleggaar, C.W. Holzapfel (later to move as professor to Rand Afrikaans University), W.T. de Kock, K.J. van der Merwe and M. Horak. Sadly, government ‘‘restructuring’’ policy, in order to become more business oriented, led to demise of the NCRL in 1987. 3. The founding of a local medium for publication of chemical research. Volume I of the ‘‘Journal of the South African Chemical Institute’’ appeared in 1948. The journal had been published previously between 1918 and 1947 but it was dedicated to scientific articles in general and not specifically chemistry. 4. The participation of large industrial concerns such as Smith-Kline & French and the Noristan Group in exploring the commercial potential of indigenous natural products. While Warren and his co-workers ‘‘dabbled’’ in fields such as the chemistry of the indigenous Euphorbia resins (Warren et al., 1949a, b), the alkaloids of the Amaryllidaceae (Warren et al., 1957) and indole alkaloids (Warren et al., 1958), his major international contribution was in the field of pyrrolizidine alkaloids (Warren, 1955, 1966). He was able to place the earlier research on Senecio alkaloids (which were associated with cirrhosis of the liver in cattle and horses) (Craig et al., 1930) on a sound scientific footing. In particular, his work on the structure and activity of the toxic (to stock) alkaloid, retrorsine (5), which occurs in the plant Senecio isatideus, deserves mention (Warren, 1949b). Not far behind Warren, in terms of international recognition, was the sophisticated work of Professor David Roux, ably assisted by Dr. Siegfried Drewes, in unravelling the structure of novel flavonoids from indigenous plants such as Colophospernum mopane (Drewes and Roux, 1966) and complex tannins from Acacia mearnsii, and related Acacias (Roux et al., 1967). Application of this knowledge was used to formulate

new glues for the South African forestry and timber industry. This work was further expanded to probe the structures of condensed tannins after Roux’s move to the University of the Orange Free State in Bloemfontein in 1968. A typical tannin precursor is shown in (6) (Roux et al., 1983). At the NCRL, Dr. Pieter Enslin extended the earlier (prior to 1944) work on toxic plants and was able to establish unambiguous structures for many of the active principles (Enslin et al., 1954; Enslin and De Kock, 1958). The inspirational leadership of Dr. Enslin had its effects on younger colleagues such as Dr. Piet Steyn and Dr. Cedric Holzapfel (Holzapfel, 1968). Dr. Steyn’s studies on mycotoxins earned him an international reputation in this area (Steyn, 1976; Steyn et al., 1977). It was largely as a result of his pioneering research that the IUPAC’s 6th International Symposium on Mycotoxins and Phytotoxins was held in Pretoria in 1985. Apart from the good NMR facilities which existed at the NCRL laboratories, the laboratory also had the good fortune to have Dr. Klaus Pachler in charge of all NMR work. Not only was he the originator of new NMR techniques such as ‘‘selective population spin inversion’’, (SPI) (Pachler and Wessels, 1977), but he was also extremely helpful in assisting with the solution of the structures of elusive natural products, e.g., the structure of vermeerin (7) (Pachler et al., 1967; Pachler and Wessels, 1977). Closure of the NCRL in 1987 was a sad day for natural products research in South Africa. The main beneficiaries of this move were the local universities who took in some of the best young researchers, e.g., Dr. James Bull, (University of Cape Town), Dr. Robert Vleggaar (University of Pretoria), Dr. Piet Steyn (Potchefstroom) and Dr Fanie van Heerden (Rand Afrikaans University). Mention has been made of the participation of commercial concerns in fostering natural products research. In the 1980s the company Noristan, based in Pretoria, carried out a large-scale screening of indigenous medicinal plants. Numerous papers dealing with promising plants, e.g., caespitin (8), a good antimicrobial from Helichrysum caespititum, and several patents arose from this work, but it did not yield a product which made the hurdle onto the international markets (Fourie et al., 1983). A spin-off of this research was that a comprehensive data base on medicinal plants was made available to the Traditional Medicines Programme (TRAMED) at the University of Cape Town on closure of the company. For the period under review (1945–1983) mention should also be made of the input to research on natural products by the group led by Professor S.H. Harper (Harper and Letcher, 1967) at the University College of Rhodesia, Salisbury (as it was known before independence). Not only did this group interact with colleagues at the regular South African Chemical Institute Conferences

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in South Africa, but they also provided a small stream of good postgraduate students to local universities.

4. 1984–2003 4.1. Into a new century and start of democratic government Up to 1984 research scientists in South Africa were funded from government funds via the Council for Scientific and Industrial Research (CSIR). From June 1984 this funding was channeled through a new body, the Foundation for Research Development (FRD), still within the CSIR ambit. In 1990, the FRD became an independent State body, no longer attached to the CSIR and with its own administrative headquarters on the periphery of the CSIR complex in Pretoria. Its first president was Dr. Reinhard Arndt from Stellenbosch, formerly of Rand Afrikaans University. Peer evaluation of all researchers in the Sciences was introduced and funding took into consideration redress measures for researchers at disadvantaged universities. Finally in 1999, the FRD was restructured to become the National Research Foundation (NRF) with Dr. Kotso Mokhele as first president. Peer evaluation was refined and funds set aside to assist researchers at previously disadvantaged universities. For natural products chemists great changes came about with the new government taking power in 1994. The fact that 80% of South Africa’s population still made use of traditional medicines, coupled with a more sympathetic attitude towards traditional healers, activated the government in promoting more research into the country’s natural resources and making generous funds available for this purpose. In particular funds were set aside to promote research (scientific, social, cultural, religious) into Indigenous Knowledge Systems. These efforts have borne fruit and more researchers are now delving into Natural Products than ever before.

5. Current active research groups in South Africa in the natural products chemistry field (1984–2003) 5.1. The KwaZulu-Natal groups During this period natural products chemistry research has been a dominant theme in the KwaZuluNatal area. Professor Siegfried Drewes of the University of Natal (Pietermaritzburg campus) has made significant contributions to the study of the phytochemistry of medicinal plants of KwaZulu-Natal. His involvement in Natural Products Research dates back to the 1960s. More recent work includes the isolation and synthesis of rooperol, (9), the anti-cancer constituent found in Hypoxis hemerocallidea (formerly H.

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rooperi) (Fig. 4), commonly known as the African potato (Drewes et al., 1984), his work on the isolation and identification of the anti-inflammatory active component, ocobullenone (10) from Ocotea bullata, the black stinkwood, and a top seller on the muthi market (Drewes et al., 1993), and, very recently, work on pyranoisoflavones, such as kraussianone I (11) which exhibits erectile-dysfunction activity, from Eriosema kraussianum (Drewes et al., 2002), indicate his important contribution to the field. Professor Karl Pegel has made a sound contribution to his area of research over the last forty years. The popular, but toxic, medicinal plant Callilepis laureola was shown to contain large amounts of atractyloside (12) thereby explaining its toxicity (Candy et al., 1977). Further studies included the isolation of numerous novel diterpenes from the Euphorbiaceae (Pegel et al., 1971; Ansell et al., 1993) and acridone alkaloids, such as tecleanthin (13) from Teclea natalensis (Pegel and Wright, 1969). His work on Hypoxis hemerocallidea (syn. H. rooperi) (Fig. 2) led to the successful marketing of an agent for threatment of BPH (benign prostata hypertrophy) (Pegel, 1984). Much later these studies resulted in the over the counter (OTC) agent Moducare1, an immune-system stimulant. Professor Colin Rogers of the University of DurbanWestville has undertaken extensive investigations of the Combretum genus of the Combretaceae family (Rogers and Verotta, 1996). After the isolation of the first triterpenoid saponin, mollic acid glucoside (14) from C. molle leaves, it was established that these triterpenoids are secreted via epidermal trichomes to form surface coatings on the leaves and fruit of all species belonging to the subgenus Combretum. The composition of the triterpenoid mixtures was found to be species specific and this has provided a chemotaxonomy link between the African Combretum and those on different continents (Rogers and Steyn, 2002). Professor D.A.H. Taylor’s research into the chemistry of the Meliaceae achieved international recognition. During his career, he isolated and identified many highly complex limonoids, such as ekebergin (15) and rohituka 7 (16) from the traditionally used Ekebergia capensis (Cape Ash) (Taylor, 1981) and Trichilia dregeana (Natal Mahogany) (Mulholland and Taylor, 1980). He provided the basis for the Natural Products Research Group which was officially recognized by the University of Natal in 1993 under the leadership of Professor D.A. Mulholland. This is the largest natural products chemistry group in the country and in the period 1991–2003 has produced some 22 MSc and 17 PhD degrees, a significant contribution to the muchneeded manpower for the chemical industry in South Africa. This group has continued to work in the field of the Meliaceae and related families (Ptaeroxylaceae and Rutaceae) of Southern and Eastern Africa (including

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Madagascar) (Mulholland et al., 2000c). Interesting compounds isolated by the group include cedmiline (17) and the anti-inflammatory microfolian (18) from the Madagascan Ptaeroxylaceae species Cedrelopsis grevei (Mulholland et al., 1999) and C. microfoliata (Koorbanally et al., 2002) respectively, delevoyin C (19) from Entandrophragma delevoyi (Meliaceae) (Mulholland et al., 2000a), and voamatin D (20) from Astrotrichilia voamata (Meliaceae) (Mulholland et al., 2000b). The group has an extensive programme investigating the chemistry and ethnobotany of the southern African Hyacinthaceae (Pohl et al., 2000, 2001) and Amaryllidaceae families (Fig. 1) in conjunction with ethnobotanist Dr. Neil Crouch of the Ethnobotany Unit of the National Botanical Institute and traditional doctor, Elliot Ndlovu (Crouch et al., 2002). 5.2. University of Venda group Dr. Jeff Mashimbye of the University of Venda is active in the research areas of flavonoids of the Compositae and their biological activities, essential oils of the Verbenaceae and antimalarial plants of the Limpopo Province (Mashimbye et al., 1999).

constituents of the Amaryllidaceae family. The work is in collaboration with the programme of the Medical Research Council Traditional Medicines Research Group, headed by Professor P. Smith, of the Department of Pharmacology, University of Cape Town (see below) and Professor C. Codina’s group at the University of Barcelona. The work has led to the isolation of interesting isoquinoline alkaloids such as obliquine (22) (Brine et al., 2002) and alkaloids with anti-plasmodial activity (Campbell et al., 1997, 1998, 2000). 5.5. Rand Afrikaans University Professor Fanie van Heerden started her career at the NCRL and worked mainly with Dr Piet Steyn on a variety of mycotoxins (Steyn et al., 1983), and toxic glycosides (Steyn et al., 1986). Subsequently at the Rand Afrikaans University, she has continued her studies on a variety of African plants, e.g. Aloe species (Van Heerden et al., 1996, 2001). 5.6. The University of Lesotho group The plants targeted for phytochemical investigation by Professor Berhanu Abegaz and his group are traded

5.3. Free State University group Research in Organic Chemistry at the Free State University (FSU), Bloemfontein has traditionally focused on the Chemistry of Natural Products, and over the past 25 years more specifically at unraveling the complex chemical characteristics of the commercially important proanthocyanidin (syn. condensed tannins) class of polyphenols. Under the leadership of the late David G. Roux and Professor Daneel Ferreira, the research team, including Professor E.V. Brandt and Professor E Malan, pioneered a semisynthetic approach to proanthocyanidin oligomers hence permitting full definition of structure and absolute stereochemistry up to the tetraflavanoid level (Young et al., 1986; Steynberg et al., 1995; Nel et al., 1999). The first stereoselective synthetic routes towards a variety of monomeric flavonoids, e.g. isoflavonoids, dihydroflavonols, flavan3,4-diols and flavan-3-ols were developed. Parallel to development of the synthetic/semisynthetic protocols a large number of new naturally occurring proanthocyanidins were identified, while the group’s expertise was also used to probe the polyphenolic profiles of traditional South African herbal beverages, such as the rooibos (Aspalathus linearis) and honeybush (21) (Cyclopia intermedia) (Kamara et al., 2003). 5.4. University of Cape Town Research at the University of Cape Town, led by Bill Campbell, has involved investigations into the chemical

Fig. 1. Boophane disticha flowering plants (Amaryllidaceae). Photograph by Dr Neil Crouch.

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materials sourced from traditional markets, and from railway and bus terminals. The identification of some of these plants has necessitated the development of micropropagation methods and the maintenance of an experimental garden. Investigated plants include those belonging to the genera Bulbine, Cassia, Dorstenia, Ledebouria, Rhus and Senna. These efforts have led to the isolation and characterization of several dozens of novel compounds such as simple anthraquinones, bianthraquinones, glycosylated and sulphated phenyl anthraquinones, isofuranonaphthoquinones, flavonoids (simple flavonoids, biflavonoids, prenylated and geranylated derivatives), an example being dinklagei B from Dorstenia dinklagei (23) (Abegaz et al., 2002). Many of these compounds possess antiplasmodial, antioxidant, nematocidal and insect anti-feedant properties. 5.7. University of Zimbabwe Natural products research in Zimbabwe, in particular in the preparation of OTC medicines, is flourishing. Emphasis is on producing medications to act as antioxidants, anti-asthmatics, anti-diabetes, anti-virals (HIV/AIDS), abortifacients, anti-hypertensive agents. Plants being used include Berchemia discolour, Lippia javanica, Swartzia madagascariensis, Amanita muscaria,

Fig. 2. Hypoxis hemerocallidae bulb (Hypoxidaceae). Photograph by Dr Neil Crouch.

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Urginea sanguinea, Myrothamnus flabellifolius (Gundidza and Chinyanganya, 1999). Two companies Aroma Chemicals (Harare) and James Mobb (Pty) Ltd, (Harare) prepare and distribute some of these medications. 5.8. University of Swaziland The natural products chemistry of plants of Swaziland is being investigated by Professors Msonthi and Makhubu from the University of Swaziland (Msonthi et al., 1999). 6. Chemical investigations into other indigenous organisms 6.1. Rhodes University The marine natural products research group in the Chemistry Department at Rhodes University has, over the last decade, investigated the bioactive natural products produced by more than 500 marine invertebrate organisms randomly collected by SCUBA off the south eastern coast of Southern Africa. Many of the endemic marine invertebrate species inhabiting the sub-tidal reefs off southern Africa are prolific producers of novel bioactive secondary metabolites. The Rhodes University

Fig. 3. Hoodia sp. (Asclepiadaceae). Photograph by Dr Neil Crouch.

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research group has published eighteen research papers (1995–2002) describing the bioactive natural products produced by western Indian Ocean marine molluscs, soft corals, sponges and ascidians (Hooper and DaviesColeman, 1995; McPhail et al., 1998; Brecknell et al., 2000; Copley et al., 2002). The large-scale collections of marine invertebrate material in this region have been carried out as collaborative efforts between Rhodes University and various US-based research organizations and pharmaceutical companies, e.g. Scripps Institution of Oceanography, SmithKline Beecham and the National Cancer Institute. 6.2. University of Stellenbosch Professor Ben Burger of the University of Stellenbosch is an internationally recognized expert for his work on the isolation and identification of insect pheromones— including pheromones from the common dung beetle and the Natal sugar cane borer (Burger et al., 1993).

7. Other researchers investigating traditionally used plants In addition to the natural products chemists involved in this area, several botanists and pharmacologists have become involved in natural products research A leading example is Professor Johannes van Staden of the University of Natal (Pietermaritzburg), whose interest lies in the screening of plants for anti-inflammatory and anti-microbial properties (Rabe et al., 2002; Sparg et al., 2002; Taylor and van Staden, 2002). Professor Marion Meyer’s (University of Pretoria) research involves conducting bioassays on anti-malarials, anti-tuberculosis compounds (Lall and Meyer, 2001; Meyer et al., 2002), erectile dysfunction agents (Drewes et al., 2002), HIV and pathogenic bacteria (Mathekga and Meyer, 1998), fungi and viruses from ethnobotanically selected South African plants. Dr Alvaro Viljoen at the University of the Witwatersrand has set up effective methods for antibacterial, antifungal and antimalarial testing of natural products (Viljoen and van Zyl, 2002) and is active in the field of essential oil analysis (Viljoen et al., 2002). Professor Ben-Erik van Wyk at the Rand Afrikaans University has been actively researching plants of the Aloe and Kniphophia families (Van Heerden et al., 1996). He has authored two books on the medicinal and poisonous plants of South Africa (see below). The programme of the Medical Research Council Traditional Medicines Research Group, mentioned earlier, is based in the Department of Pharmacology, University of Cape Town. Based on traditional usage information, more than one hundred candidate plant species were collected, and assayed for antiplasmodial

and antimycobacterial activity At a later stage, assays for the study of viral skin disorders, cytotoxicity, immunostimulatory activity and acetylcholinesterase inhibition, were developed and applied to further plant collections. Several promising leads have been pursued to the point of the isolation and structural elucidation of the active compounds in conjunction with Mr. Bill Campbell. Professor Kobus Eloff’s group at the Phytomedicine Department, University of Pretoria’s research involves improving ethnoveterinary practices and developing, from natural products, medications which will enhance the quality of life of rural communities. Emphasis is on plants that can be used to combat parasitic stock diseases (Eloff and Kotze, 2002). Dr. Q. Johnson of the University of Western Cape is engaged in studies of indigenous medicine for reproductive health with emphasis on safety, efficacy, mode of action and application as natural therapeutics (Johnson and Veith, 2001). Professor J.A. Syce, a pharmacologist at the same institution, is conducting research into indigenous plants used to combat asthma (Syce et al., 1998). Research at the Agricultural Research Institute (Infruitec-Nietvoorbij) into the health benefits of rooibos tea (Aspalathus linearis) and tea from the honey bush (Cyclopia intermedia) is being undertaken by Dr. E. Joubert in conjunction with Professor E.V. Brandt of the University of the Free State (Joubert et al., 1997,1998). This research has been important in the commercialization of these two natural products.

Fig. 4. Hypoxis hemerocallidea. Drawing by Dr Tanza Crouch.

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7.1. Books in this period, 1984–2003 The following books have stimulated the interest of South African phytochemists to delve deeper into investigating the nature of local natural products:  Hutchings, A., Scott, A.H., Lewis, G., Cunningham, A.B., 1996. Zulu medicinal plants. University of Natal Press, Pietermaritzburg  Van Wyk, B.E., Van Oudtshoorn, B., Gericke, N., 1997. Medicinal Plants of South Africa. Briza Publications, Pretoria.  Van Wyk, B.E., Van Heerden, F.R., Van Oudtshoorn, B., 2002. Poisonous Plants of South Africa. Briza Publications, Pretoria.  Hedburg, I, Stangard, F., 1989. Traditional medicine in Botswana—traditional medicine plants. Ipeleng Publishers.

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some 300 HIV positive patients and it is her objective to provide support and clinical care as well as identifying affordable management protocols, using medicinal plants in conjunction with standard forms of treatment for people living with HIV AIDS. Medicinal plants featured are: Artemisia afra, Bulbine species, Centella asiatica, Lippia javanica, Siphonochilus aethiopia, Sutherlandia frutescens and Warburgia salutaris (bark and leaves) (personal communication; Hutchings, 2003).

9. Conclusion The field of natural product chemistry is an extremely active one in Southern Africa. The recent award of a substantial National Research Foundation Innovation Fund grant to facilitate drug discovery by bringing together some of the country’s leading chemists, ethnobotanists, pharmacologists and medical researchers bodes well for the future.

8. Commercial products Several plant extracts derived from South African medicinal plants are available commercially: 1. ‘‘Moducare’’, originally from Hypoxis, to boost the immune system and cure arthritis. 2. Sutherlandia frutescens whole dried plant material now on the market to combat muscle wasting and general debility in HIV patients. (Produced by Phyto Nova in Cape Town). 3. Hoodia currorii (Fig. 3)—The Khoi/San plant developed by CSIR as an appetite suppressant as early as 1967 with Professor Fanie van Heerden being one of the researchers involved. Now licensed to Pfizer for $32 million (via Phytopharm as an intermediary). The sale of the license by the CSIR generated much controversy, but a royalty-sharing agreement has now been reached with the San community. 4. A variety of ointments which are either antiinflammatory, anti-bacterial, antiviral or antioxidant, and are derived from indigenous plants, are undergoing activity tests. Almost all South African Universities now have researchers active in this area with teams consisting of phytochemists, ethnobotanists, pharmacologists, traditional healers and medical researchers. 5. Rooibos and honey bush teas are widely consumed locally and a thriving international market for these products has been developed. Typical of the type of work being undertaken in many areas of southern Africa, is the research of Mrs. Ann Hutchings from the University of Zululand. At a clinic she has started at the rural Ngwelezane Hospital she has

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Dulcie A. Mulholland Natural Products Research Group, School of Pure and Applied Chemistry, University of Natal, Durban, 4041, South Africa E-mail address: [email protected] Siegfried E. Drewes School of Chemical and Physical Sciences, University of Natal, Private Bag XO1, Scottsville, 3209, Pietermaritzburg, South Africa E-mail address: [email protected]

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Dulcie Mulholland obtained her PhD degree in 1980 from the University of Natal in Durban working with Professor David Taylor on the limonoids from Trichilia dregeana. She returned to the University to take up an academic position in 1991 and continued her work on the chemistry of the Meliaceae and related families. She heads the Natural Products Research Group at the University, is Professor of Organic Chemistry and is Head of the School of Pure and Applied Chemistry. Her research interests have expanded to include the chemistry of the Rutaceae, Amaryllidaceae and Hyacinthaceae families.

Siegfried Drewes obtained his PhD from Rhodes University and a DSc from the University of Natal. His interest in natural products was kindled during his PhD years working with Professor David Roux on the tannins of Acacia mearnsii at the Leather Industries’ Research Institute in Grahamstown. He joined the University of Natal in 1969, had a brief sojourn into protein chemistry (insulin derivatives) with Professor Donald Sutton and then reverted to natural products again, specifically the chemistry of muthi plants (indigenous plants used by the traditional healers). His work in this area culminated in the award of an ‘‘A’’ rating by the Foundation for Research Development. In 1995 he retired as Head of the Department of Chemistry, but has stayed on in the Department as Honorary Research Associate. He rates among his most memorable achievements the isolation of ocobullenone from Ocotea bullata, rooperol from Hypoxis hemerocallidea, and the kraussianones from Eriosema kraussianum.