Plants as Sources of Drugs - ACS Publications - American Chemical

Chapter 12

Plants as Sources of Drugs

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A. Douglas Kinghorn and Eun-Kyoung Seo Program for Collaborative Research in the Pharmaceutical Sciences, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois, 833 South Wood Street, Chicago, IL 60612-7231

Plants have a historically important role as sources of prescription drugs in western medicine, and their active principles also serve as templates for synthetic drug optimization and provide intermediates that are used in the production of semi-synthetic drugs. Worldwide, hundreds of higher plants are cultivated for substances useful in medicine and pharmacy. Although the anticancer agent taxol (paclitaxel) is thefirstnaturally occurring plant-derived drug to have gained the approval of the U.S. Food and Drug Administration for more than 25 years, analogs of other plant constituents such as artemisinin, camptothecin, and forskolin are currently under development for drug use in western medicine. Another recent development has occurred in Western Europe, where there is currently a well-developed phytomedicinal market, with extractives of many plants being used for therapeutic purposes. An underlying concern with the production of plant-derived drugs is the question of supply, which must be stable and reliable, and frequently necessitates cultivation rather than collection in the wild. Information on the cultivation, constituents, and therapeutic uses of two examples of important medicinal plants (Panax ginseng; Korean ginseng and Ginkgo biloba; Ginkgo) will be provided in this chapter.

For millenia, drugs from higher plants (gymnosperms and angiospenns) have been used to cure or alleviate human sickness, and, until relatively recently, were the major sources of medicines. The vast majority of plant drugs now used are classified as secondary metabolites of the producing organism, and, as such, they are derived from primary metabolites biosynthetically but have no apparent function in the primary metabolism of the plant. In the past two centuries, many plant secondary metabolites

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In Agricultural Materials as Renewable Resources; Fuller, G., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1996.


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have been purified and structurally characterized because of the medicinal properties of their species of origin, affording numerous compounds of medicinal and pharmaceutical importance (1-6). Many of the natural drugs presently used were obtained from plants used as toxins in their native habitats, such as physostigmine, dtubocurarine, and certain cardiac glycosides (7). Other plant drugs have been obtained as a result of folkloric use for medicinal purposes, as exemplified by digitoxin, morphine, pilocarpine, and quinine (7). Plant secondary metabolites have two important additional roles, in being used as templates for the design and synthesis of completely novel drug entities, as well as serving as source material for the semisynthesis of medicinal agents (1-7). Importance of Plant-Derived Drugs in Modern Medicine It has been estimated that 80% of the world's population who live in developing countries depend chiefly on traditional medical practices, inclusive of the use of medicinal higher plants for their primary health care needs (1,4). Some of these systems are very well developed, such as Chinese traditional medicine (1,4). Farnsworth and colleagues have determined that about 120 plant-derived substances from some 90 species are used as drugs in one or more countries, with 74% of these having been discovered as a result of laboratory studies conducted on the active principles of medicinal plants used in traditional medicine (1,4). Examples of wellestablished drugs of plant origin used in various countries throughout the world are shown in Table I, and it is to be noted that most of these are still produced commercially by cultivation, extraction, and purification, with only the more structurally simple compounds successfully synthesized for the marketplace. Largescale production of plant secondary metabolites by tissue-culture techniques has attracted a great deal of interest, but thus far none of the plant drugs listed in Table I are produced commercially in this manner (8). In addition to pure drug entities of plant origin, extractives of medicinal plants containing partially purified secondary active principles are still widely used. Examples include standardized extractivesfromAtropa belladonna and Datura metel (with the solanaceous tropane alkaloids present used as mydriatics and anticholinergics), and from Cephaelis acuminata and C. ipecacuanha (having isoquinoline alkaloids that are commonly used as emetic agents in the treatment of domestic accidental poisonings), andfromDigitalis purpurea (containing cardiotonic glycosides, which are still of major use in the treatment of congestive heart failure) (1,3,4). Drugs derived from higher plants, both in the pure and the crude extractive form, are contained in up to 25% of the prescriptions dispensed in community pharmacies in the United States, at an estimated value of some $8 billion in 1980 (1,4). In addition to their value as drugs per se, plant secondary metabolites have a considerable history of use as lead compounds for the design of synthetic drugs, and perhaps the best examples are cocaine and morphine, which in turn have served as templates for the synthesis of novel local anesthetics and analgesics. Other examples are atropine, physostigmine, and quinine, which have been utilized as chemical models for the design and synthesis of anticholinergics, anticholinesterases, and antimalarials,


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TABLE I. SOME PLANT-DERIVED DRUGS WITH CLINICAL USE Acetyldigoxin Aescin Ajmalicine Allantoin Andrographolide Anisodamine Anisodine Arecoline Atropine Benzyl benzoate Berberine Borneol Bromelain Caffeine Camphor Chymopapain Cocaine Colchicine Curcumin Danthron Deslanoside Deserpidine Digitoxin Digoxin L-DOPA Emetine Ephedrine Etoposide Galanthamine Gitalin Hydrastine Hyoscyamine Kawain Khellin Lanatosides A, B, and C a-Lobeline Menthol


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respectively (7-7). Plant constituents may also be employed as raw materials for the commercial production of drugs by partial synthesis, as exemplified by the production of hormones from diosgenin, hecogenin, and stigmasterol, for use in oral contraceptive formulations (7-7). Only a small proportion (probably 10-15%) of the 250,000 or so higher plants that occur worldwide have so far been subjected to any form of scientific study concerning the chemical composition andBiol.ogicalproperties of their secondary metabolites (1,4,5,9). This is especially true for plants of the tropical rainforests, where about one half or 125,000 of the world's flowering plants occur, and it has been estimated recently that only about one-eighth (48) of the potential drugs therein (about 375) have so far been discovered (10). As a result of the devastation of the tropical rainforests, which has been well-publicized, there is now a very great interest in preserving both the genetic resources and theInd.igenousknowledge associated with the use of medicinal plants in these regions (9). The issues of fostering scientific collaboration between scientists in western and developing countries, as well as providing appropriate compensation to persons in tropical countries where the greatest plant biodiversity occurs, have become increasingly important in the context of the drug discovery process from higher plants (9). The majority of the plant drugs presently on the market are alkaloid salts and glycosides, and hence reasonably watersoluble, a property which has facilitated their laboratory and clinical evaluation. However, most of the newer drugs, drug candidates, and lead compounds from plants have less than optimum water solubility properties, and some have proven to be problematic in terms of their stability or supply. New therapeutic agents of plant origin, which have either been recently introduced onto the market, or else have the promise of being introduced soon, are considered in the next section of this chapter. New Medicinal Agents of Plant Origin The semi-synthetic lignan, etoposide, derived from podophyllotoxin, a constituent of Podophyllum peltatum and P. emodi rhizomes, has been used for over 10 years as a cancer chemotherapeutic agent for the treatment of small-cell lung and testicular cancers (77). Very recently a second podophyllotoxin analog, teniposide (1) (Vumon®), has been introduced in the United States for use in combination chemotherapy to treat patients with refractory childhood acute lymphoblastic leukemia (72). Another recently introduced derivative, the tartrate salt of vinorelbine (2) (5'-noranhydrovinblastine, Navelbine®), a semi-synthetic derivative of the bisInd.ole alkaloids, vinblastine and vincristine, which are in turn constituents of the leaves of Catharanthus roseus. Vinblastine and vincristine are well-established anticancer agents themselves, and have been used in therapy for over 30 years (5,77). Vinorelbine (2) was developed by a French pharmaceutical company (6,13), and isInd.icatedforfirst-linetherapy of nonsmall-cell lung cancer, either alone or in combination with cisplatin (73). There is no question, however, that the plant-derived drug that has captured the attention of both the scientific community and the lay public to the greatest extent in recent years is the nitrogenous diterpenoid, paclitaxel (3; TAXOL®; previously known in the scientific literature as taxol). Paclitaxel was approved by the FDA for the



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treatment of refractory ovarian cancer in late 1992 and for refractory breast cancer in 1994. This is the first chemically unmodified plant secondary metabolite to have been introduced to the U.S. drug market in nearly 30 years (5,14,15). Paclitaxel was discovered more than 20 years ago as an antitumor constituent of the bark of Taxus brevifolia (Pacific or western yew), by M.E. Wall and M.C. Wani of Research Triangle Institute in North Carolina (14,15). Later Horwitz and co-workers demonstrated that the compound has a unique mechanism of action in being an antimitotic agent which stabilizes microtubules and prevents depolymerization (14,15). Clinical trials on paclitaxel began in the United States in 1984, and proved encouraging, so much so that the clinical demand created a supply crisis for paclitaxel when obtained by isolation and extraction from Τ brevifolia bark (14-16). It was calculated that the amount of dried T. brevifolia bark required to produce 1 kg of paclitaxel is 15,000 pounds, and in 1991 over 1.6 million pounds of the bark of this species were harvested from Washington and Oregon for the production of paclitaxel (16). However, this large-scale collection of bark from naturally growing T. brevifolia specimens caused environmental concerns (15). Accordingly, various proposals have been put forth for the alternative production of large enough quantities of paclitaxel to both meet clinical demands and allay the environmental outcry. Several semisynthetic routes have been proposed for paclitaxelfromditerpenoid building blocks (14,15), and the compound has actually been totally synthesized by the Holton and Nicolaou groups (14,15). Other methods of paclitaxel production are direct extraction and isolation from ornamental Taxus cultivars, plant cell culture, and fermentation of an endophytic fungus (a novel Taxomyces species) that biosynthesizes this compound de novo (16). However, because the molecule of paclitaxel (3) has 11 chiral centers, and the methods of total synthesis are complex and inVol.ve over 25 steps each, future production of this drug will inVol.ve partial synthesis from natural starting materials such as 10-deactylbaccatin III (4) and baccatin III (5), which are extractable in large quantities from renewable ornamental species such as Taxus baccata (European yew) and T. wallichiana (Himalayan yew) (14-16). Approval has been given by the FDA for the production of paclitaxel by semisynthesis from diterpenoid precursors produced by Taxus species (17). To provide the paclitaxel diterpenoid synthetic intermediates, millions of seedlings of the cultivar Taxus X media "Hicksii" are being grown in nurseries in the United States and Canada each year (18). A semi-synthetic analog of paclitaxel that has been developed in France is docetaxel (Taxotere®), and this has shown good progress in clinical trials to date (14,15). According to a company profile of the manufacturer of docetaxel, this compound is produced from yew trimmings obtained from English country houses, French cemeteries, and in theInd.iansubcontinent (19). Another group of plant-derived compounds with high potentiality for the treatment of cancer are analogs of the quinoline alkaloid, camptothecin (7), obtained from the Chinese tree, Camptotheca acuminata. The alkaloid was isolated and structurally characterized about 30 years ago by Wall and Wani, when it was found to exhibit antileukemic and antitumor activity (20). After an early disappointing clinical trial on the water-soluble sodium salt of camptothecin in the early 1970s in the United States, interest in camptothecin and its analogs increased substantially when these compounds were found to target specifically the enzyme DNA topoisomerase I (21).



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Following successful murine xenograft preclinical evaluation, at the present time camptothecin and four of its more water-soluble analogs are in clinical trials in several countries as anticancer agents, comprising 9-amino-20(iS)-camptothecin (8), topotecan (9), irinotecan (10, CPT-11), and 7-[(4-methylpiperazino)methyl]-10,11(ethylenedioxy)-20(S)-camptothecin (11), and several of the free base or salt forms of these compounds have shown significant activities in patients with refractory malignancies (20-22). Recently, irinotecan has been approved as an anticancer agent in Japan and France (M.C. Wani, Research Triangle Institute, Research Triangle Park, North Carolina, private communication). C. acuminata is native to several provinces including Szechwan in southern parts of the People's Republic of China, and requires frost-free conditions for growth (20,21). To meet the present demand, camptothecin is obtained from C. acuminata cultivated inInd.iaand the People's Republic of China (16). Camptothecin is extracted from C. acuminata cultivated at Ishigaku Island in southern Japan for the production of irinotecan after chemical modification, for use in Japan (23). A group of plant-derived compounds based on the sesquiterpene lactone endoperoxide artemisinin (12; also known as qinghaosu), a constituent of the Chinese medicinal plant, Artemisia annua, offer good clinical prospects for the treatment of malaria (24,25). Artemisinin is itself poorly soluble in water and has only a short plasma half-life, but the sodium salt of the hemisuccinate ester (sodium artesunate, 13) is readily water soluble. The latter compound is available in the People's Republic of China and several southeast Asian countries for the treatment of falciparum malaria. A more stable analog, also used as an antimalarial in the same countries as 13 is artemether (14), the methyl ether derivative of artemisinin (24,25). A major pharmaceutical company is planning to introduce artemether to the world market (26). Other derivatives of arterrusinin with potential for clinical use are arteether (15) and sodium artelinate (16) (24,25). In terms of its production to meet the clinical demand, artemisinin is harvested from wild stands in the People's Republic of China, with varieties in Sichuan Province apparently affording yields of up to 0.5% (w/w). Plant growth improvement trials are also being undertaken in several countries, including Australia (Tasmania),Ind.ia,the Netherlands, Saudi Arabia, Switzerland, the United States, and Yugoslavia (27). Forskolin (17), a diterpenoid of the labdane type, is a consituent of the Ind.ian plant, Coleus forskohlii, which has a history of use in ayurvedic medicine. This compound exhibits potent adenylate cyclase activating activity, and has been found to have hypotensive properties, with cardiotonic, platelet-aggregation inhibitory, and spasmolytic effects (28,29). While theBiol.ogicalactivities of the parent compound have been known for some time, a number of forskolin analogs with potential for drug use have been developed inInd.ia(29). Of these, NKH 477 (18) is a derivative with an aminoacyl substituent that is water-soluble and is undergoing clinical trial in Japan, in the form of its hydrochloride salt, as a cardiotonic. HIL 568 (19) reduces the intraocular pressure of rabbits, and is being developed for the treatment of glaucoma (29).


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Examples of Two Medicinal Plants [Panax ginseng (Korean Ginseng) and Ginkgo biloba (Ginkgo)] Used as European Phytomedicines In addition to the above-mentioned promising pure compounds from plants with present drug use or potential for drug use, standardized extractives of plants with therapeutic efficacy are employed as in several countries in western Europe as "phytomedicines" (30-32). Phytomedicines, otherwise known as herbal remedies, are powdered vegetable drugs as well as various types of extracts made from powdered drugs. In Germany the Federal Health Agency (Bundesgesundheitsamt) has set up the so-called Commission Ε for Human Medicine, Section on Phytotherapy, to evaluate herbal drugs and produce monographs describing drug safety and efficacy, which are employed in the licensing of phytomedicines (30,32). Whereas in countries such as Germany, phytomedicines are supplied as prescription drugs, several of the same preparations are sold in the United States in health food stores without therapeutic claims (30). About 150 phytomedicines are listed as being beneficial by the European Scientific Cooperative on Phytotherapy (ESCOP) (57), and in a standard German textbook on herbal drugs recently translated into English, monographs of 181 of these drugs are provided (32). Most of the European phytomedicines are produced for commercial purposes by cultivation, and to further emphasize such medicinal plants as being renewable resources obtained through agriculture, two examples have been selected, with both being of major market significance. The first of these is Panax ginseng, a plant which is native to eastern Asia, which has been used for thousands of years as a tonic and panacea (32-35). P. ginseng is used as a herbal tea drug in Germany as a tonic to combat feelings of lassitude and debilitation, a lack of energy and/or an inability to concentrate, and during convalescence (32). Ginseng is an adaptogen, and thereby enables the adaptation of the subject to external or internal disturbances (32). The experimental evidence for the clinical activity of ginseng is equivocal, although an immunostimulant activity has been demonstrated in laboratory animals, and it is apparent that the clinical benefits may not take place immmediately (32). The active principles of P. ginseng are considered to be the ginsenosides, which are triterpene saponins, whose aglycones are of two major types. For example, ginsenosides Rfy (20), Rb (21), and Rc (22) are based on the sapogenin, 20(iS)-protopanaxadiol and ginsenosides Re (23), Rgj (24), and Rhj (25) are based on the sapogenin, 20(5)protopanaxatriol (32-34). Many other ginsenosides have been structurally elucidated from Panax species, and it has been shown that non-triterpenoidal constituents of ginseng also exhibitBiol.ogicalactivity (32). In Korean ginseng, ginsenosides Rb Rc, and Rgj are the most abundant triterpene saponin constituents, but different ginsenoside profiles occur in different parts of the plant (55). Since the various ginsenosides have differentBiol.ogicalactivities, it is important that their concentration levels are standardized in commercially used P. ginseng preparations. Panax ginseng is a perennial herb that grows best in shaded areas, and, although this is also cultivated for the drug market in Japan, the People's Republic of China, and Russia, much of the worldwide production is obtained from Korea, where modem farming and factory procedures are employed. Commercial Korean ginseng is now 2

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produced almost entirely by organized cultivation (33). To cultivate ginseng of high quality, rather strict conditions must be adhered to. The annual average temperature should be in the range 0.9-13.8 °C, and in the summer, 20-25°, with a rainfall of 1,200 mm/year, and little or no snow. Dispersed sunlight is required (1/8 to 1/13 of direct sunlight), and the soil should be at pH 5.5-6.0, and free of insect infestation. Hilly exposures to the north or northeast are preferable, but flat locations can be used for ginseng cultivation if the drainage is good (36). The aerial parts of the plant die back each year, and the roots are harvested in September of the fourth through the sixth year of growth, depending upon the quality of ginseng desired (33,36). Two major ginseng products are produced in Korea, namely, red ginseng and white ginseng, which are prepared by different methods of drying (33,37). After six years of growth, the fleshy roots of P. ginseng are about 35 cm long, of weight usually in the range 70-100 g (up to 300 g has been recorded), and the diameter of the roots is about 3 cm (36). The roots are dried in the shade, washed, and cut lengthwise into two. Red ginseng is prepared by wrapping with a cloth, steaming for about three hours, and drying in the shade (one day) and with hot air (20 days). White ginseng is dried in the shade (ten days) and with hot air (20 days) (36). The processed material is sold commercially in the form of whole or powdered roots, and as tablets, capsules, tea bags, oils, and extractives (33). Other varieties of ginseng are Chinese, Japanese, and American, representing a total of three to six distinct species of Panax (33). American ginseng (Panax quinquefolius), for example, is an important specialty crop in Wisconsin, of value $50 million per year (38). Of all the plants used as phytomedicines in Europe, probably the most important one is Ginkgo biloba (Ginkgo), for which the leaves are supplied as a standardized extract (EGb 761) used to treat cerebral blood flow insufficiency and other conditions (30,39). The gingko market in Europe is large, and in a recent year amounted to some $500 U.S. (39). Ginkgo leaf preparations are available in at least 30 countries (40). G. biloba is a gymnosperm native to the People's Republic of China and Japan that is one of the oldest known species on earth. The plants are extremely long-lived, and may grow as trees to more than 30 meters tall. While therapy with Ginkgo preparations can be traced back to Chinese traditional medicine, the more modem usage began in Germany in the mid-1960s (40). EGb 761 is an extractive of G. biloba leaves produced with acetone and water, followed by the removal of strongly lipophilic compounds and condensed polyphenols, and it has been suggested that it is the combined effects of the various leaf secondary metabolite constituents which are responsible for the observed clinical activities of Ginkgo. These constituents are complex and embrace various terpenoid lactones [e.g., ginkgolides A-C, J and M (26-30) and bilobalide (31)], biflavonoids (e.g., armentoflavone, 32; bilobetin, 33; ginkgetin, 34; isoginkgetin, 35; sciadopitysin, 36; 5'-methoxybilobetin, 37), as well as flavonol glycosides (e.g., mono-, di-, and triglycosides of kaempferol, isorhamnetin, and quercetin), coumaric acid esters of flavonols, and other phenols (39-41). The standard plant extract EGb 761 contains 24% w/w of flavonoids and 6% w/w of terpene lactones (39). Short reviews have appeared recently on the botany (42), constituents (41), pharmacology (43), and standardization (39) of G. biloba. The ginkgolides, which are unusual diterpenoids possessing sixfive-memberedrings and aterf-butylgroup that are found only in G.



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biloba, are potent inhibitors of platelet-activating factor (PAF), a substance inVol.ved in the process of inflammation (44). The range of clinicalApplicationsfor which extract EGb 761 is officially used in Europe includes headache, hearing loss, mood disturbance, short-term memory loss, tinnitus, and vertigo, when associated with degenerative angiopathy and cerebrovascular insufficiency (39,40). In addition to their prescription use in Europe, Ginkgo preparations with low terpene lactone and flavonoid glycoside contents are used in certain countries for self-medication to treat symptoms such as loss of concentration and memory, reduced mental and physical efficiency, and vertigo (39). It is of interest to note that large amounts of the Ginkgo biloba leaves currently used in European phytomedicines are cultivated in the United States, at a 1,200-acre plantation in Sumter, South Carolina. Cultivation of G. biloba began at this site in 1982, and seedlings are planted in 40 inch rows with about 10,000 plants per acre. The seedlings are in turn grown from seed purchased in Korea, Japan, or the People's Republic of China, and cultivated in a nursery for two years. More mature plants, which are from six to 13 years old when harvested, are pruned annually, and shaped into a bush or shrub form. They are appropriately irrigated and fertilized, and are resistant to insect attack. The leaves of the plant are harvested mechanically in July through September of each year, and after being artificially dried and then baled, they are transported to Europe for further processing (C.H. Johnson, Garnay, Inc., Sumter, South Carolina, private communication). Summary and Conclusions Plants have long been important sources of medicinal agents, and their secondary constituents have served to provide chemical ideas for the molecular design of many synthetic drugs. The prospects for the discovery of further drugs from plants has recently attracted significant attention from major scientific publications outside this specialist field (45,46). This wider interest in plant drugs has been attributed to the undisputed efficacy of the plant-derived drugs already known, theirfrequentnovel mechanisms of biochemical action, their value in drug semi-synthesis, and their use as extractives in phytomedicine (46). Because of the well-established chemical and Biol.ogical diversity of plant constituents, coupled with the present availability of highthroughput bioassays and sensitive methods for compound structure elucidation, there has been an increased effort in plant drug discovery inIndustrial,academic, and Industrial laboratories in many countries (e.g., 5,46,47). However, despite the sophistication of modem organic synthesis, it is not always economically feasible to produce plant secondary metabolite drugs commercially by synthesis. Accordingly, most plant drugs are currently produced by cultivation, and may be used clinically either as semi-purified extractives or as pure crystalline substances. The cultivation of these plants as renewable resources tends to provide more stable supplies of plant drugs than collection in the wild. It has recently been suggested, however, that in future, plant sources of new drugs should be cultivated in plantations in the countries where they were originally collected, in order to return some of the revenues that their commercial exploitation will generate (9).


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Acknowledgment The authors are grateful to Dr. Cecil H. Johnson, Garnay, Inc.,IndustrialFarming, Sumter, South Carolina, for providing certain unpublished data on the cultivation of Ginkgo biloba.


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Plants as Sources of Drugs - ACS Publications - American Chemical

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