《天然药物化学》课程参考文献（天然药物研究与开发）Plant-Derived Natural Products as Leads for Drug Discovery.pdf

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

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

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