Plant-Derived Natural Products as Leads for 24 Drug Discovery Li Pan,Esperanza J.Careache de Blanco, and A.Douglas Kinghorn also serve as prototype drug molecules,known Introduction as"lead compounds",and as pharmacological probes.to help better understand biochemical Natural product molecules having their origin and physiological mechanisms. from plants,microorganisms,and animals have In thischapter,some successful drugs derived had an irreplaceable role throughout the last from plant secondary metabolites in their original 200 years in treating and preventing diseases,or modified forms,and other substances,currently and continue to serve as important leads in under clinical trial as drug candidates.as well as modemn drug discovery Several volumes and several additional compounds used as biochemical reviews published recently have focused on this probes afforded from plants,will be described. topic I1-61.A considerable proportion of the A general description of the imp ortance and natural products used as drugs is derived from f plants in drug discovery will terrestrial plants.which offer an invaluable and still incor exhausted re based on th e us oy huma s,phe Role of Plants in Drug Development research on plant has been facilitated by the Medicinal plants have been used as a major source development of relevant technologies including new isolation methods,more sensitive spectro- of drugs for thousands of years in human history. and even today they are basis of the systematic scopic techniques for structural determination, as well as specific high-throughput bioassay traditional medicine practices in many countries systems.Plant-derived bioactive compounds,in all over the world.The first recorded literature on medicinal plants can he traced hack to an earlier addition of being developed directly as drugs, age of human history such as the Atharvaveda (2000 BC)in India.the Divine Farmer's Herb L.Pan,EJ.Carcache de Blanco, Root Classic (3000 BC)in China.and the Eber andA.D.Kinghom(☒) vision of Me Ch that the r loped OH 43210 USA e-mails:pan.106@osu.edu; carcache-de-blan.I@osu.edu;kinghorn.4@osu.edu 72 medicinal plants have been introduced into A.E.Osbourn and V.Lanzotti(eds),Plant-derived Natural Products, 547 DOI 10.1007/978-0-387-85498-4 24.Springer Science+Business Media,LLC 2009
Plant-Derived Natural Products as Leads for Drug Discovery Li Pan , Esperanza J. Carcache de Blanco , and A. Douglas Kinghorn Introduction Natural product molecules having their origin from plants, microorganisms, and animals have had an irreplaceable role throughout the last 200 years in treating and preventing diseases, and continue to serve as important leads in modern drug discovery. Several volumes and reviews published recently have focused on this topic [1– 6] . A considerable proportion of the natural products used as drugs is derived from terrestrial plants, which offer an invaluable and still incompletely exhausted resource for this purpose. In addition, profound ethnomedical knowledge based on the use of medicinal plants by humans has been accumulated for thousands of years. In the last few decades, pharmaceutical research on plants has been facilitated by the development of relevant technologies including new isolation methods, more sensitive spectroscopic techniques for structural determination, as well as specific high-throughput bioassay systems. Plant-derived bioactive compounds, in addition of being developed directly as drugs, also serve as prototype drug molecules, known as “lead compounds”, and as pharmacological probes, to help better understand biochemical and physiological mechanisms. In this chapter, some successful drugs derived from plant secondary metabolites in their original or modified forms, and other substances, currently under clinical trial as drug candidates, as well as several additional compounds used as biochemical probes afforded from plants, will be described. A general description of the importance and perspective of plants in drug discovery will also be given. Role of Plants in Drug Development Medicinal plants have been used as a major source of drugs for thousands of years in human history, and even today they are basis of the systematic traditional medicine practices in many countries all over the world. The first recorded literature on medicinal plants can be traced back to an earlier age of human history, such as the Atharvaveda (2000 BC) in India, the Divine Farmer’s HerbRoot Classic (3000 BC) in China, and the Eber Papyrus (1550 BC) in Egypt [7, 8] . It is evident that the modern drug industry has been developed to a considerable degree as a result of plant-based traditional medicines. A review published in 2001 indicated that 88 active compounds isolated from 72 medicinal plants have been introduced into 24 L. Pan, E.J. Carcache de Blanco, and A.D. Kinghorn () Division of Medicinal Chemistry and Pharmacognosy , College of Pharmacy, The Ohio State University , Columbus , OH 43210 , USA e-mails: pan.106@osu.edu; carcache-de-blan.1@osu.edu; kinghorn.4@osu.edu A.E. Osbourn and V. Lanzotti (eds.), Plant-derived Natural Products, 547 DOI 10.1007/978-0-387-85498-4_24, © Springer Science + Business Media, LLC 2009
548 L.Panetal 24 modem drug therapy.with many of them being plant-derived small organic molecules and other sidered as the roduets with an imnortant potential their ethopha ticholin suppre employed in the pharmaceutical industry ove colchicine (antigout).ephedrine (bronchodilator). the last 2 decades to satisfy the need for very morphine (analgesic),pilocarpine(parasympatho- large numbers of compounds demanded in mimetic),andphysostigmine(cholinesterase inhib- high-throughput screens (HTS),the results itor)are still being widely used today [101. have not been as promising as expected,and A whole new era for drug discovery opened the number of new chemical entities intro- up in the early nineteenth century,triggered by duced annually as produced by this method has the isolation of morphine a pharmacologically actually declined i3.171.A combination of active comnound from the plant medicine onium natural products and combinatorial chemistry Later.compounds from plants such as atropine has been initiated in recent vears.In this case (Atropa belladonna),cocaine (Erythroxylum the latter serves as a technique to optimize the ca)ephedrine (Enhedra spp.）,digitoxin and qu structure of existing active natural compounds (Digitalis gnn】 epuneandhen to nev ved asdrugs(25] ounds isolated from an a s the clin only for en and pac as potent medici al tre ents,but a for com nelping unde man diseases by disclos pounds,affording nume structural analogs ing the key role that these molecules play,and as new pharmaceutical agents,such as artem by promoting the development of pharmacology,isinin and the opiate derivatives.In addition to medicinal chemistry as well as organic chem- their medicinal use,some secondary metabo istry [].Asa result of the further purification of lites from plants have also served as powerful drugs such as artemisinin,digoxin,paclitaxel, “pharmacological tools”to help explain the vinblastine,and vincristine from plants in the mechanismsunderlying human diseases[21-24]. twentieth century.the use of plant extractives in Today.drug discovery from plants is based prescriptions such as tincture of belladonna was mainly on bioactivity-guided isolation,and groups gradually replaced by pure single chemical enti- of scientists with different research backgrounds ies like ats nine including botany.biochemistry.pharma Plantsand be da medicinal aries of small- npou are required in this enterprise [1-14,25,26. al diversity probably be in a sy laboratory [11-14].As secon iry meta these compounds have been elaborated in living Plant Natural Products as Drugs organisms by complex enzyme systems devel oped during a long evolutionary process.It is Despite the"synthetic revolution"in the phar- apparent that these natural products present maceutical industry.medicinal plants are still more“dug-like”or "biologically friendly involved in the primary health care of a large pro- molecular qualities than many purely synthetic portion of the population in the world,especially compounds.These intrinsic properties provide in developing countries 9.Bioactivity-guided
548 L. Pan et al. 24 modern drug therapy, with many of them being considered as the active principle responsible for their ethnopharmacological use [9] . Some of these plant-derived therapeutic agents, such as atropine (anticholinergic), codeine (cough suppressant), colchicine (antigout), ephedrine (bronchodilator), morphine (analgesic), pilocarpine (parasympathomimetic), and physostigmine (cholinesterase inhibitor) are still being widely used today [10] . A whole new era for drug discovery opened up in the early nineteenth century, triggered by the isolation of morphine, a pharmacologically active compound from the plant medicine opium. Later, compounds from plants such as atropine ( Atropa belladonna ), cocaine ( Erythroxylum coca ), ephedrine ( Ephedra spp.), digitoxin ( Digitalis purpurea ), and quinine ( Cinchona spp.) were purified and then served as drugs [2, 4, 5] . These discoveries are considered important not only for introducing new single chemical entities as potent medicinal treatments, but also for helping understand human diseases by disclosing the key role that these molecules play, and by promoting the development of pharmacology, medicinal chemistry as well as organic chemistry [8] . As a result of the further purification of drugs such as artemisinin, digoxin, paclitaxel, vinblastine, and vincristine from plants in the twentieth century, the use of plant extractives in prescriptions such as tincture of belladonna was gradually replaced by pure single chemical entities like atropine. Plants and other organisms may be regarded as libraries of small-molecule secondary metabolite organic compounds with considerable structural diversity, which would otherwise probably be unavailable in a synthetic chemical laboratory [11– 14] . As secondary metabolites, these compounds have been elaborated in living organisms by complex enzyme systems developed during a long evolutionary process. It is apparent that these natural products present more “drug-like” or “biologically friendly” molecular qualities than many purely synthetic compounds. These intrinsic properties provide plant-derived small organic molecules and other natural products with an important potential role in modern drug discovery [15, 16] . Although combinatorial chemistry has been employed in the pharmaceutical industry over the last 2 decades to satisfy the need for very large numbers of compounds demanded in high-throughput screens (HTS), the results have not been as promising as expected, and the number of new chemical entities introduced annually as produced by this method has actually declined [3, 17] . A combination of natural products and combinatorial chemistry has been initiated in recent years. In this case the latter serves as a technique to optimize the structure of existing active natural compounds to new agents [17– 20] . Active compounds isolated from plants can serve directly as therapies in clinical use, like morphine, atropine, quinine and paclitaxel, or as prototype biologically active “lead” compounds, affording numerous structural analogs as new pharmaceutical agents, such as artemisinin and the opiate derivatives. In addition to their medicinal use, some secondary metabolites from plants have also served as powerful “pharmacological tools” to help explain the mechanisms underlying human diseases [21– 24] . Today, drug discovery from plants is based mainly on bioactivity-guided isolation, and groups of scientists with different research backgrounds including botany, biochemistry, pharmacology, pharmaceutics, pharmacognosy, medicinal chemistry, organic chemistry and toxicology are required in this enterprise [12– 14, 25, 26] . Plant Natural Products as Drugs Despite the “synthetic revolution” in the pharmaceutical industry, medicinal plants are still involved in the primary health care of a large proportion of the population in the world, especially in developing countries [9] . Bioactivity-guided
4 Pant-Derived 549 fractionation can often lead to the isolation of sickness in the form of a transdermal patch. active principles of these medicinal plants,and Both of these tropane alkaloids have psychoac- some of those chemical entities with acceptable tive effects as a result of their ability to pene- pharmaceutical qualities can be developed as trate the blood-brain barrier [7,27,28]. drugs in their original forms directly.These Nicotine (4),an agonist on the nicotinic ace- include compounds on the therapeutic market tylcholine receptor(nAChR)found in Nicotiana that have been used for many years as important tabacum (tobacco),is used pharmaceutically clinical agents mainly in the treatment of can- for smoking cessation 1291.Analogs of nicotine cer.central nervous system disorders.cardio- are considered promising for the treatment of vascular diseases. and infectious disease neurodege rative conditions like Alzheimer's -420.nh 蒸 ant-deri ed dn will be Morphine (5)and codeine (n majo each sed from the immatur Atropine (1)[a racemic mixture of (+) and (-)-hyoscyamine (2)]and scopolamine and codeine can interact with opioid receptors [(-)-hyoscine](3)are tropane-type alkaloids distributed in brain tissues and the periphery, found in certain plants in the Solanaceae (night- and are most widely used as narcotic analgesics. shade)family used medicinally for centuries in with codeine also having an antitussive effect Europe,such as Atropa belladonna,Hyos-[4.25,32]. eyamus niger,and Datura stramonium [The Galantamine (7,Razadyne",Reminyl", antispasmodic activities of atropine are due to Nivalin)is a recently approved drug for the competitive antagonism of acetylcholine at the treatment of early-onset Alzheimer's disease muscarinic receptor site.Scopolamine is also 1121.Galantamine (or galanthamine)is an an anticholiner agent, and most co Amaryllidaceae-type alkaloid first purified ed for the preve n of nausea and motion from the snowdrop(Galanthus CH2OH 】HCH2oH 。C 。 2.(-)-hyoscyamine Ro. OH Meo 人N 4.nicotin &聚omc 7.galantamine
24 Plant-Derived Natural Products as Leads for Drug Discovery 549 fractionation can often lead to the isolation of active principles of these medicinal plants, and some of those chemical entities with acceptable pharmaceutical qualities can be developed as drugs in their original forms directly. These include compounds on the therapeutic market that have been used for many years as important clinical agents mainly in the treatment of cancer, central nervous system disorders, cardiovascular diseases, and infectious diseases [11– 14, 20] . In this section, some important plant-derived drugs in their unmodified forms will be mentioned, with a brief description about the plant origin and pharmaceutical use in each case. Atropine ( 1 ) [a racemic mixture of (+)- and (-)-hyoscyamine ( 2 )] and scopolamine [(-)-hyoscine] ( 3 ) are tropane-type alkaloids found in certain plants in the Solanaceae (nightshade) family used medicinally for centuries in Europe, such as Atropa belladonna , Hyoscyamus niger , and Datura stramonium [7] . The antispasmodic activities of atropine are due to competitive antagonism of acetylcholine at the muscarinic receptor site. Scopolamine is also an anticholinergic agent, and most commonly used for the prevention of nausea and motion sickness in the form of a transdermal patch. Both of these tropane alkaloids have psychoactive effects as a result of their ability to penetrate the blood-brain barrier [7, 27, 28] . Nicotine ( 4 ), an agonist on the nicotinic acetylcholine receptor (nAChR) found in Nicotiana tabacum (tobacco), is used pharmaceutically for smoking cessation [29] . Analogs of nicotine are considered promising for the treatment of neurodegenerative conditions like Alzheimer’s disease [30, 31] . Morphine ( 5 ) and codeine (methylmorphine) ( 6 ), two major morphinan-type alkaloids with an isoquinoline skeleton, are extracted from opium, the dried milky sap released from the immature fruits of poppies ( Papaver somniferum ). Morphine and codeine can interact with opioid receptors distributed in brain tissues and the periphery, and are most widely used as narcotic analgesics, with codeine also having an antitussive effect [4, 25, 32] . Galantamine ( 7 , Razadyne®, Reminyl®, Nivalin®) is a recently approved drug for the treatment of early-onset Alzheimer’s disease [12] . Galantamine (or galanthamine) is an Amaryllidaceae-type alkaloid first purified from the snowdrop ( Galanthus woronowii ) in N O CH2OH O 1. atropine N O CH2OH O 2. (-)-hyoscyamine N O CH2OH O O H 3. scopolamine [(-)-hyoscine] H 4. nicotine N N H N H HO O H RO 5. R = Me codeine 6. R = H morphine N O OH MeO 7. galantamine
多 L.Panetal 24 theearly 1950s and ter found in pther plants and other species.Quinine (1)was the first malaria ove chol mp and inbihi asmodium The discovery of quinin European settlers from the harmfu receptors (nAChRs)[33-36].The market need effects of this fatal illness,and greatly facilitated for galantamine is now met by the total synthe- colonization in many tropical and subtropical sis of this compound [36]. areas of the world [40].Quinine exerts its activ- The demand for the legalization of Cannabis ity by inhibiting the heme polymerase of the sativa (marijuana)for medicinal use has repre- parasitic host,and still shows some efficacy sented an interesting controversy in recent years today as an antimalarial agent in cases where because of the possibility of abuse [37].synthetic drugs fail due to parasite resistance 2, Cannabidiol (CBD,8)and A-trans-tetrahydro- 6,41].Quinidine(11),has some use as a cardiac cannabinol (THC.9),two active cannabinoids antiarrhythmic by affecting ion channels [2.411 of mariiuana.have been approved recently in Artemisinin("qinghaosu")(12),a sesquiter Canada as ingredients of an ne lactone po o an unusual endor ide marketed as Sativ ex®to alleviate the ound dis red in the People's ed by multiple sclerosis (MS).Effor oublic of China fromr nade to introduce ex to other long bee used as ries in the enear future [38,39]. the f feve a Quin aining quinoline rings in as an optio r th t of heir molecules,are obtained from Cinchona spp. chloroquine-resistant malana in China and some 8.cannabidiol(CBD) 9.Atrans-tetrahydrocannabinol (THC) "O 10.quinine 11.quinidine
550 L. Pan et al. 24 the early 1950s, and later found in other plants of the family Amaryllidaceae [34] . Galantamine can improve cerebral function by acting as a cholinergic agent, and inhibits acetylcholinesterase and modulates nicotinic acetylcholine receptors (nAChRs) [33– 36] . The market need for galantamine is now met by the total synthesis of this compound [36] . The demand for the legalization of Cannabis sativa (marijuana) for medicinal use has represented an interesting controversy in recent years because of the possibility of abuse [37] . Cannabidiol (CBD, 8 ) and D9 - trans -tetrahydrocannabinol (THC, 9 ), two active cannabinoids of marijuana, have been approved recently in Canada as ingredients of an oromucosal spray marketed as Sativex® to alleviate the pain caused by multiple sclerosis (MS). Efforts are being made to introduce Sativex® to other countries in the near future [38, 39] . Quinine ( 10 ) and quinidine ( 11 ), two diastereomeric alkaloids containing quinoline rings in their molecules, are obtained from Cinchona spp. and other species. Quinine ( 10 ) was the first effective treatment for falciparum malaria, an often fatal parasitic disease caused by several species of plasmodium. The discovery of quinine relieved European settlers from the harmful effects of this fatal illness, and greatly facilitated colonization in many tropical and subtropical areas of the world [40] . Quinine exerts its activity by inhibiting the heme polymerase of the parasitic host, and still shows some efficacy today as an antimalarial agent in cases where synthetic drugs fail due to parasite resistance [2, 6, 41] . Quinidine ( 11 ), has some use as a cardiac antiarrhythmic by affecting ion channels [2, 41] . Artemisinin (“qinghaosu”) ( 12 ), a sesquiterpene lactone possessing an unusual endoperoxide bridge, is a compound discovered in the People’s Republic of China from Artemisia annua , which has long been used as a traditional medicinal plant for the treatment of fever. As a naturally occurring antimalarial, artemisinin may be employed as an option for the treatment of chloroquine-resistant malaria in China and some 9. Δ9 -trans-tetrahydrocannabinol (THC) O OH 8. cannabidiol (CBD) HO OH 11. quinidine N N H OH MeO H N N H OH H MeO 10. quinine
4 Pant-Derived 551 other countries in Asia [42].Artemisinin exerts Paclitaxel (15,Taxol)is a diterpenoid its activity through a unique mechanism by based on the taxane nucleus,possessing an acting on the heme complex [43].However,the essential oxetane ring and with one of the use of artemisinin as a monotherapy antimalarial substituent groups containing a nitrogen atom. agent is no longer recommended,since this This compound was first isolated from the bark might lead to parasite resistance to this entire of Taxus brevifolia (Pacific yew)[47].As a compound class「441 chemotheraneutic anticancer agent paclitaxel In the nineteenth century,digitoxin (13).a inhibits mitosis by acting as a microtubule a solated from Digitalis rily for the treatm and ne r48,49 e tre for d The limit the eight n(14)is an was onc obstacle active cardiotonic glycoside that was purifie synthetic and biological methods wer deve from Digitalis lanata subsequent to the oped to solve this problem,as will be discussed discovery of digitoxin.These two drugs exhibit later in this chapter. a positive inotropic effect by inhibiting the Vinblastine (16,Velban,Alkaban-AQR) activity of ATPase and cation transport.thus and vincristine(17,Oncovin)are structurally resulting in the increase of Ca levels in the closely related indole-dihydroindole dimers myocytes [461. (bisindolealkaloids),isolatedfromCatharanthus H OH OH OH 12.artemisinin 13R, 14.R1=OH igitoxin digox NH HO 15.paclitaxel(taxol) 16.R =CH3 vinblastine 17.R=CHO vincristine
24 Plant-Derived Natural Products as Leads for Drug Discovery 551 other countries in Asia [42] . Artemisinin exerts its activity through a unique mechanism by acting on the heme complex [43] . However, the use of artemisinin as a monotherapy antimalarial agent is no longer recommended, since this might lead to parasite resistance to this entire compound class [44] . In the nineteenth century, digitoxin ( 13 ), a major cardioactive steroid glycoside, was isolated from Digitalis purpurea , commonly known as purple foxglove. This plant proved to be an effective treatment for dropsy caused by congestive heart failure in the late eighteenth century in England [45] . Digoxin ( 14 ) is another active cardiotonic glycoside that was purified from Digitalis lanata subsequent to the discovery of digitoxin. These two drugs exhibit a positive inotropic effect by inhibiting the activity of ATPase and cation transport, thus resulting in the increase of Ca 2+ levels in the myocytes [46] . Paclitaxel ( 15 , Taxol ® ) is a diterpenoid based on the taxane nucleus, possessing an essential oxetane ring and with one of the substituent groups containing a nitrogen atom. This compound was first isolated from the bark of Taxus brevifolia (Pacific yew) [47] . As a chemotherapeutic anticancer agent, paclitaxel inhibits mitosis by acting as a microtubule stabilizer and has been used in the clinic primarily for the treatment ovarian cancer, breast cancer, and non-small cell lung cancer [48, 49] . The limited availability of the plant source of paclitaxel was once a considerable obstacle in the development of this drug, until new semisynthetic and biological methods were developed to solve this problem, as will be discussed later in this chapter. Vinblastine ( 16 , Velban®, Alkaban-AQ®) and vincristine ( 17 , Oncovin®) are structurally closely related indole-dihydroindole dimers (bisindole alkaloids), isolated from Catharanthus O O O O O 12. artemisinin H H O O OH H H H O O OH O R1 O OH O O OH HO 13. R1 = H digitoxin 14. R1 = OH digoxin HO NH O HO O O O AcO OH AcO O O O H 15. paclitaxel (taxol) 16. R = CH3 vinblastine 17. R = CHO vincristine N N H OH H OAc COOMe R MeO N H N MeOOC OH
级 L.Panetal 24 roseus,also known as Vinca rosea (Madagascar based on natural products,12%"natural product and 12%synthetic d mainly to treat dif which the ph emodeled ugh they have efficiency against atural pro other forms of cancer. Those two anticancer agents act as mitotic inhibitors by binding to required to enhance therapeutic potency,to dimeric tubulin,and then leading to the failure increase bioavailability,to remove unpleasant of microtubule assembly in the metaphase stage side effects,and to help compensate for a short- [50-521. age in a natural product drug supply,or to derive different bioactivities.This section will focus on examples of semi-synthetic drugs of plant origin. Semi-synthetic Drugs Based on Plant A series of artemisinin-based semisynthetic Secondary Metabolites antimalarial derivatives.with all of them main- taining the key endoperoxide bridge,such as sm-ynthetic derivatives as dug arteether(18),artemether(19),artes unate (20) eloped from n ral duct lead and dihydr isinin(21),ha ninete to in nd the t ry and ed by dr gs like nl.Amo aspirin(acetyl id).From the 01 dihydroartemis sinin (artenimol), the potential of plant-de comp sidered as a common ac metabolite of leads in drug discovery has been realized on artemisinin derivatives [53,54].Currently numerous occasions [8].A survey released artemisinin-based therapies combined with recently revealed that over 40%of the new standard antimalarials such as amodiaquine. small-molecular single chemical entity drugs sulfadoxine-pyrimethamine,mefloquine,and introduced to the market from 1981 to 2006 lumefantrine are recommended by the World are natural product derivatives,with 28%of Health Organization(WHO)as first-line therapies them being chemical semi-synthetic modifications for malaria [55,56]. 18.R=Et arteether 19.R Me artemethe 20.R=3 COOH artesunate 21.R=H dihydroartemisinin
552 L. Pan et al. 24 roseus , also known as Vinca rosea (Madagascar periwinkle). Vinblastine and vincristine are used mainly to treat different forms of leukemia, although they have efficiency against several other forms of cancer. Those two anticancer agents act as mitotic inhibitors by binding to dimeric tubulin, and then leading to the failure of microtubule assembly in the metaphase stage [50– 52] . Semi-synthetic Drugs Based on Plant Secondary Metabolites The use of semi-synthetic derivatives as drugs developed from plant natural product lead compounds began at the end of the nineteenth century and may be exemplified by drugs like aspirin (acetyl salicylic acid). From then on, the potential of plant-derived compounds as leads in drug discovery has been realized on numerous occasions [8] . A survey released recently revealed that over 40% of the new small-molecular single chemical entity drugs introduced to the market from 1981 to 2006 are natural product derivatives, with 28% of them being chemical semi-synthetic modifications based on natural products, 12% “natural product mimics”, and 12% synthetic compounds in which the pharmacophore modeled was that of a natural product [20] . Synthetic optimization of the naturally occurring compounds is often required to enhance therapeutic potency, to increase bioavailability, to remove unpleasant side effects, and to help compensate for a shortage in a natural product drug supply, or to derive different bioactivities. This section will focus on examples of semi-synthetic drugs of plant origin. A series of artemisinin-based semisynthetic antimalarial derivatives, with all of them maintaining the key endoperoxide bridge, such as arteether ( 18 ), artemether ( 19 ), artesunate ( 20 ), and dihydroartemisinin ( 21 ), have been designed to improve the water solubility and the metabolic stability of artemisinin [53, 54] . Among them, dihydroartemisinin (artenimol), is considered as a common active metabolite of artemisinin derivatives [53, 54] . Currently, artemisinin-based therapies combined with standard antimalarials such as amodiaquine, sulfadoxine-pyrimethamine, mefloquine, and lumefantrine are recommended by the World Health Organization (WHO) as first-line therapies for malaria [55, 56] . O O O O OR 18. R = Et 19. R = Me 20. R = 21. R = H arteether artemether artesunate dihydroartemisinin H H O COOH
4 Pant-Derived 553 As mentioned before,the market demand of of this compound begins from(--shikimic the anticancer drug.paclitaxel(15,Taxol)was acid (25),which serves as the key intermediate threatened initially by an unsustainable natural in the biosynthesis of a variety of aromatic com- supply,which relied mainly on extracting this pounds in plants and microorganisms 121 compound from the bark of the slow-growing Shikimic acid was first isolated from the plant Pacific yew tree,from which it is produced only Illicium anisatum(Japanese"shikimi")in 1885. in a very low vield I571.Although the total syn- and is abundant in the star aniseed (Illicium thesis of paclitaxel has been described,this is verum)and the plant genus Liquidambar still inefficient when considered the extensive ("sweetgum)[65,66].In order to ov rcome the market need [5860].10-Deacetylbaccatin III shortage e of the natural so oure of shikimic acid (2).which is available high yicldiol fermentation of this substa the le 1as was intrd fully alterna as a sem tive method of cently, of paclitaxel by the major pharm al m synthetic metho phosphat ufacturer.Bristol-Myers Squibb (B-MS)[611.independent of shikimic acid has been devel Docetaxel(23),a related taxane anticancer drug oped [68]. can also prepared from 10-deacetylbaccatin III Nitisinone (26,OrfadinR)is the first drug (22)[62]. approved in Europe for the treatment of heredi- Oseltamivir phosphate (24,Tamiflu),a tary tyrosinemia type 1 (HT-1),a rare genetic neuraminidase inhibitor,is administered orally metabolic disorder caused by a deficiency of for the treatment and prevention of influenza A fumarylacetoacetatehydrolase(FAH),anenzyme and B virus infections,and stockpiling of this involved in the metabolism of tyrosine 69]. drug has been proposed to counter the threat of a Nitisinone is a derivative of leptospermone (27). pandemic such as avian flu 63.641.One synthesis an effective herbicide present in the bottlebrush HO H HO HO 22.10-deacetylbaccatin III 23.docetaxel 4.osetamivir phosphat 25.()-shikimic acid 26.nitisinone
24 Plant-Derived Natural Products as Leads for Drug Discovery 553 As mentioned before, the market demand of the anticancer drug, paclitaxel ( 15 , Taxol®) was threatened initially by an unsustainable natural supply, which relied mainly on extracting this compound from the bark of the slow-growing Pacific yew tree, from which it is produced only in a very low yield [57] . Although the total synthesis of paclitaxel has been described, this is still inefficient when considered the extensive market need [58– 60] . 10-Deacetylbaccatin III ( 22 ), which is available with a relatively high yield from the leaves of other renewable yew species, such as Taxus baccata L., was introduced as a semi-synthetic precursor compound of paclitaxel by the major pharmaceutical manufacturer, Bristol-Myers Squibb (B-MS) [61] . Docetaxel ( 23 ), a related taxane anticancer drug can also prepared from 10-deacetylbaccatin III ( 22 ) [62] . Oseltamivir phosphate ( 24 , Tamiflu®), a neuraminidase inhibitor, is administered orally for the treatment and prevention of influenza A and B virus infections, and stockpiling of this drug has been proposed to counter the threat of a pandemic such as avian flu [63, 64] . One synthesis of this compound begins from (−)-shikimic acid ( 25 ), which serves as the key intermediate in the biosynthesis of a variety of aromatic compounds in plants and microorganisms [2] . Shikimic acid was first isolated from the plant Illicium anisatum (Japanese “shikimi”) in 1885, and is abundant in the star aniseed ( Illicium verum ) and the plant genus Liquidambar (“sweetgum”) [65, 66] . In order to overcome the shortage of the natural source of shikimic acid, fermentation of this substance by metabolically engineered Escherichia coli strains has been developed successfully as an efficient alternative method of production [67] . Recently, a total synthetic method for oseltamivir phosphate independent of shikimic acid has been developed [68] . Nitisinone ( 26 , Orfadin®) is the first drug approved in Europe for the treatment of hereditary tyrosinemia type 1 (HT-1), a rare genetic metabolic disorder caused by a deficiency of fumarylacetoacetate hydrolase (FAH), an enzyme involved in the metabolism of tyrosine [69] . Nitisinone is a derivative of leptospermone ( 27 ), an effective herbicide present in the bottlebrush 23. docetaxel HO O O O O HO OH AcO O H N H O O OH O 22. 10-deacetylbaccatin III HO HO O O O HO OH AcO O H O NH2.H3PO4 F3C NO2 HN O O O HO COOH HO OH 24. oseltamivir phosphate 25. (-)-shikimic acid O O O O O O O 26. nitisinone 27. leptospermone
554 L.Panetal 24 plant Callistemon).Nitisinone can compe alcoholism a ti of 4-hydroxyphenyl pyrvat xygenase(HPPD), [76].Dextro an upstream enzyme o Dromrhan (3 FAH,to prevent accumulation of toxic tyrosine metabolites that lead to liver and kidney failure Podophyllotoxin (34).is a lignan constituent [69-711. of Podophyllum resin,produced from the North Opiates,narcotic compounds extracted or American mayapple (Podophyllum peltatum) derived from opium,are a remarkable source of and the Himalayan species Podophyllum hexan- lead compounds for their potent pharmaceutical drun 178.791.As a result of its considerable effects such as analgesics,antitussives and toxicity,extensive chemical modification work ataractics.and of which many synthetic deriva-has been done to improve the pharmaceutical tives have been prepared [72].Apomorphine profile of podophyllotoxin.Etoposide(35).ten- (28)a donamine agonist derivative from mor- iposide (36).and etopophos (etoposide phos- phine(5)but without analgesic properties like phate,the prodrug of etoposide)are successful ntly red as a the drugs for Parkinson's disease 7.Hvdro derived from podophyllotoxin 1791.Instead of acti inhibitors narcotic agent derived fro /30 nly ves 35 and 36 exert their such activities by rugs to reli e pair [741 Naloxon (31)and altrexone (32)are both opioid receptor antago to treat lympho nas,acute leu emia,small cel nists.Naloxone is used as a treatment for opioid lung cancer,and testicular cancers [78-80 28.apomorphine 29.thebaine 30.hydrocodon 31.nal 33.dextromethorphan
554 L. Pan et al. 24 plant Callistemon citrinus [70] . Nitisinone can interfere with tyrosine catabolism as a competitive inhibitor of 4-hydroxyphenyl pyruvate dioxygenase (HPPD), an upstream enzyme of FAH, to prevent accumulation of toxic tyrosine metabolites that lead to liver and kidney failure [69– 71] . Opiates, narcotic compounds extracted or derived from opium, are a remarkable source of lead compounds for their potent pharmaceutical effects such as analgesics, antitussives and ataractics, and of which many synthetic derivatives have been prepared [8, 72] . Apomorphine ( 28 ), a dopamine agonist derivative from morphine ( 5 ) but without analgesic properties like morphine, was recently approved as a therapy for Parkinson’s disease [73] . Hydrocodone ( 30 ) is a narcotic agent derived from thebaine ( 29 ) and is commonly combined with other analgesics such as acetaminophen and ibuprofen as drugs to relieve pain. [74] . Naloxone ( 31 ) and naltrexone ( 32 ) are both opioid receptor antagonists. Naloxone is used as a treatment for opioid overdose [75] , while naltrexone can be used to treat alcoholism as well as opiate addiction [76] . Dextromethorphan ( 33 ) is a non-narcotic opiate derivative that is widely used as an overthe-counter cough-suppressant [77] . Podophyllotoxin ( 34 ), is a lignan constituent of Podophyllum resin, produced from the North American mayapple ( Podophyllum peltatum ) and the Himalayan species Podophyllum hexandrum [78, 79] . As a result of its considerable toxicity, extensive chemical modification work has been done to improve the pharmaceutical profile of podophyllotoxin. Etoposide ( 35 ), teniposide ( 36 ), and etopophos (etoposide phosphate, the prodrug of etoposide) are successful anticancer drugs derived from podophyllotoxin [79] . Instead of acting as microtubule inhibitors in the same manner as the lead compound 34 , derivatives 35 and 36 exert their anticancer activities by acting as inhibitors of the enzyme topoisomerase II, and together are widely used to treat lymphomas, acute leukemia, small cell lung cancer, and testicular cancers [78– 80] . HO N H HO 28. apomorphine O N HO HO O 31. naloxone H O N H MeO O 30. hydrocodone H O N MeO MeO 29. thebaine H O N HO O 32. naltrexone HO H N MeO H 33. dextromethorphan H
4 Plant-Derived dsfor 55 OH MeO OMe OH 34.podophyllotoxin 35.R=Me etoposide teniposide Coleus forskohlii (Lamiaceae),a traditional Use of Plant-Derived Natural Products medicinal plant used in India for the treatment as"Pharmacological Probes" of heart disease and asthma[84].Asa hype ten e agent with spa ardiot and A number of plant secondary metabolites have anti-pate ation activi been found to be nacological probes”or "bioche AC) tion of cA a potent pharmacological tool widely used in Genistein (37),an estrogenic isoflavone investigating the catalytic mechanism of AC present in soybean (Glycine max),is a protein and the regulation of cAMP [86-88]. tyrosine kinase (PTK)inhibitor,and has been Quercetin(39)is one of the most common used as a probe to study the interaction between natural occurring flavonoids and is found in PTK and cyclic nucleotide-gated (CNG)chan-many fruits and vegetables,such as apples and nels [81,82].Genistein is currently under clinical onions.It is well known for its antiinflamma- trial for its angiogenesis-inhibiting activity [83].tory,antioxidant,and antiplatelet aggregation Forskolin (38),also known as coleonol,is a activities [89.911.Quercetin can induce a wide labdane diterpene isolated from the roots of spectrum of cellular events by interacting with a or OH H 37.genistein 38.forskolin 39.quercetin
24 Plant-Derived Natural Products as Leads for Drug Discovery 555 Use of Plant-Derived Natural Products as “Pharmacological Probes” A number of plant secondary metabolites have been found to be valuable “pharmacological probes” or “biochemical tools” to help target various receptors as well as to explain cellular processes and assist with the elucidation of different kinds of molecular targets. Genistein ( 37 ), an estrogenic isoflavone present in soybean ( Glycine max ), is a protein tyrosine kinase (PTK) inhibitor, and has been used as a probe to study the interaction between PTK and cyclic nucleotide-gated (CNG) channels [81, 82] . Genistein is currently under clinical trial for its angiogenesis-inhibiting activity [83] . Forskolin ( 38 ), also known as coleonol, is a labdane diterpene isolated from the roots of Coleus forskohlii (Lamiaceae), a traditional medicinal plant used in India for the treatment of heart disease and asthma [84] . As a hypertensive agent with spasmolytic, cardiotonic and anti-platelet-aggregation activity, forskolin can directly activate adenylate cyclase (AC), a target enzyme of multiple G-protein-coupled receptors (GPCRs), leading to the intracellular accumulation of cAMP [85, 86] . This property makes it a potent pharmacological tool widely used in investigating the catalytic mechanism of AC and the regulation of cAMP [86– 88] . Quercetin ( 39 ) is one of the most common natural occurring flavonoids and is found in many fruits and vegetables, such as apples and onions. It is well known for its antiinflammatory, antioxidant, and antiplatelet aggregation activities [89, 91] . Quercetin can induce a wide spectrum of cellular events by interacting with a O OMe MeO OMe O OH O O 34. podophyllotoxin O OH MeO OMe O O O O O O O OH HO R etoposide teniposide S 35. R = Me 36. R = 37. genistein O O OH OH HO O O O O OH H OH OH 38. forskolin O OH OH OH HO OH O 39. quercetin
556 L.Panetal 24 almodulin(CaM)[8991] and vin This flavo (17),m usedasbiolog al probes incan cleic acids and otein orescence emiss ion [92.93].Thi stabilization of microtubules [98-102] property allows quercetin to be a valuable,sen- Capsaicin (42),a pungent principle in chili sitive,and selective spectroscopic probe to trace peppers (Capsicum spp.),as well as the skin phenol-binding complexes in cellular systems irritant,resiniferatoxin(43),from the latex of and help clarify the relevant molecular functions Euphorbia resinifera,have been used to probe 92-941. the transient receptor potential (TRP)channels Phorbol esters.tetracyclic diterpenoids natu- and the vanilloid receptors responsible for the rally occurring in some plants of the family pain sensation caused by heat.This has led to Euphorbiacaeae,such as Croton tiglium,show the successful isolation of the first nociceptive protein kinase C(PKC)inhibition activity,and receptor,TRPVI (transient receptor potential are also known for their skin-irritant and tumor- channel.vanilloid subfamily member 1)1103 motion pr perties 195 961 The most abundant 104].Capsaicin-containing hol ester derivative 12-0-tetr for the orbol-13-acetate (TPA)(40),is used th ard tumo pro offul-erm car n animal models The intera of sever po: -op e targeting agents like col neuropathic pain,and muse chicine (41),as well as certain anticancer agents is currently under clinical trial [106 40.12-0-tetradecanoylphorbol-13-acetat 41.colchicine oA HO- Meo OMe OH 42.capsaicin 43.resiniferatoxin
556 L. Pan et al. 24 number of signaling molecules such as protein kinases, NF- k B, and calmodulin (CaM) [89– 91] . This flavone can bind to intracellular targets, such as nucleic acids and proteins and exhibits specific fluorescence emission [92, 93] . This property allows quercetin to be a valuable, sensitive, and selective spectroscopic probe to trace phenol-binding complexes in cellular systems and help clarify the relevant molecular functions [92– 94] . Phorbol esters, tetracyclic diterpenoids naturally occurring in some plants of the family Euphorbiacaeae, such as Croton tiglium , show protein kinase C (PKC) inhibition activity, and are also known for their skin-irritant and tumorpromotion properties [95, 96] . The most abundant C. tiglium phorbol ester derivative, 12- O -tetradecanoylphorbol-13-acetate (TPA) ( 40 ), is used as a standard tumor promoter in animal models of full-term carcinogenesis [97] . Some microtubule targeting agents like colchicine ( 41 ), as well as certain anticancer agents mentioned before, such as podophyllotoxin ( 34 ), paclitaxel ( 15 ), vinblastine ( 16 ) and vincristine ( 17 ), may be used as biological probes in cancer research. Thus, paclitaxel acts as a promoter of stabilization of microtubules [98– 102] . Capsaicin ( 42 ), a pungent principle in chili peppers ( Capsicum spp.), as well as the skin irritant, resiniferatoxin ( 43 ), from the latex of Euphorbia resinifera , have been used to probe the transient receptor potential (TRP) channels and the vanilloid receptors responsible for the pain sensation caused by heat. This has led to the successful isolation of the first nociceptive receptor, TRPV1 (transient receptor potential channel, vanilloid subfamily member 1) [103, 104] . Capsaicin-containing creams are now available as nonprescription pain-relievers for the treatment of post-therapeutic neuralgia [105] . The internal use of capsaicin for the treatment of severe post-operative pain, post-traumatic neuropathic pain, and musculoskeletal diseases is currently under clinical trial [106] . O H O OH OH OH O H H O O 40. 12-O-tetradecanoylphorbol-13-acetate NH O O OMe MeO MeO OMe 41. colchicine H H N HO MeO O 42. capsaicin 43. resiniferatoxin O OH H H O O O O O OMe OH
