Viewpointviewpoint Natural Products and Drug Discovery

viewpointviewpoint Natural products and drug discovery

Can thousands of years of ancient medical knowledge lead us to new and powerful drug combinations in the fight against cancer and dementia? Hong-Fang Ji, Xue-Juan Li & Hong-Yu Zhang

he medicinal use of natural prod- as a basis for drug development. The modern emetic and how to use olive oil to improve ucts—compounds that are derived tools of chemistry and biology—in partic wound healing (Castiglioni, 1985). Roman Tfrom natural sources such as plants, ular, the various ‘-omics’ technologies—now physicians built on this extensive know animals or micro-organisms—precedes allow scientists to detail the exact nature of ledge and added their own insights and recorded human history probably by thou- the biological effects of natural compounds experience. Pedanius Dioscorides (circa sands of years. Palaeoanthropological stud- on the human body, as well as to uncover 40–90 aD) compiled De Materia Medica, ies at the cave site of Shanidar, located in possible synergies, which holds much prom- which described the dosage and efficacy of the Zagros Mountains of Kurdistan in Iraq, ise for the development of new therapies about 600 plant-derived medicines and laid have suggested that more than 60,000 years against many devastating diseases, including the foundations of pharmacology in Europe ago, Neanderthals might have been aware dementia and cancer. (Wermuth, 2003). Galen (129–200 aD), of the medicinal properties of various another famous Greek physician and pharm plants, as evidenced by pollen deposits in wing to the diverse biological acist, recorded 540 plant-derived medicines one of the graves at the site (Solecki, 1975). activities and medicinal potentials and demonstrated that herbal extracts con- Over the ensuing millennia, humankind Oof natural products, nearly every tain not only beneficial components, but discovered and made use of an enormous civilization has accumulated experience also harmful ingredients (Cai, 1992; Cheng range of natural compounds; the latest ver- and knowledge of their use. The oldest med & Zhen, 2004). sion of the Dictionary of Natural Products ical text comes from ancient Mesopotamia, (DNP; http://dnp.chemnetbase.com) has circa 2600 BC, and is written on hundreds …the switch away from natural just over 214,000 entries. of clay tablets in cuneiform. It describes Throughout our evolution, the impor- approximately 1,000 plants and plant- products to combinatorial tance of natural products for medicine and derived substances, such as the oils of Cedrus chemistry during the 1990s health has been enormous. Since our earliest species (cedar), the resin of Commiphora might have led to the current ancestors chewed on certain herbs to relieve myrrha (myrrh) and the juice of the poppy paucity of new drug candidates pain, or wrapped leaves around wounds seed Papaver somniferum (Newman et al, in the development pipeline… to improve healing, natural products have 2000). Many of these herbs and formulations often been the sole means to treat diseases are still used today. The ancient Egyptian and injuries. In fact, it has only been during Ebers Papyrus, dating from around 1550 BC, Natural product-based medicines also the past decades that natural products have contains about 800 complex prescriptions flourished in the Orient. Charaka Samhita, taken a secondary role in drug discovery and more than 700 natural agents such as the first treatise devoted to the concepts and drug development, after the advent of Aloe vera (aloe), Boswellia carteri (frank- and practice of Indian Ayurveda, was writ- molecular biology and combinatorial chem- incense) and the oil of Ricinus communis ten around 900 BC and contains 341 plant- istry made possible the rational design of (castor) (Zhong & Wan, 1999). The famous derived medicines. The Sushruta Samhita chemical compounds to target specific mol- Greek physician, Hippocrates of Cos (circa (circa 600 BC) was mainly devoted to ecules. The past few years, however, have 460–377 BC), collected more than 400 surgical practices, but also described 395 seen a renewed interest in the use of natural natural agents and described their use in his medicinal plants and 57 animal-derived compounds and, more importantly, their role Corpus Hippocraticum. He mentioned using products (Dev, 1999). melon juice as a laxative, described the di Traditional Chinese medicine (TCM) Throughout our evolution, the uretic effect of the juice from Ornithogalum is also famous for its extensive use of nat caudatum (squill) and detailed how to use ural products. The most primitive Chinese importance of natural products an extract from Atropa belladonna as an medicinal book, Wu Shi Er Bing Fang— for medicine and health has anaesthetic. He also advised using an extract which translates to Prescriptions for Fifty- been enormous of Veratrum album (white hellebore) as an Two Diseases—was compiled around

350 BC and lists 247 natural agents and espite the wide use of medicinal …it remains an important about 150 combinatorial drug formulae, plants in the Orient and Occident, challenge to find biologically along with practical advice regarding the Dtheir effective components—the active compounds and to develop properties, efficacies and synergies of nat specific identity of the chemicals that had ural medicines (Wan & Zhong, 1990; Jiao the desired therapeutic effects—remained these into new drugs, even if one & Wang, 2005). The monograph Shen all but unknown until the eighteenth and uses nature for inspiration Nong Ben Cao Jing (Shen Nong Materia nineteenth centuries. However, early doc- Medica) was compiled during the Eastern tors, such as Galen, did understand that estimates that about 60% of the drugs that Han dynasty (25–220 AD) and documented various natural products contained differ- are now available—including household 365 agents, including 252 medicinal ent compounds that would each affect the names such as artemisinin, camptothecin, plants and 67 medicinal animals (Gao, human body differently. lovastatin, maytansine, paclitaxel, peni 2004). The therapeutic effects of many of Modern chemistry has ushered in a new cillin, reserpine and silibinin—were either these agents have been confirmed by subs era for the study and use of natural prod- directly or indirectly derived from natural equent medical practice (Gao, 2004), such ucts. Analytical and structural chemistry products. Moreover, natural products have as the use of Coptis chinensis (coptis root) have provided the tools to purify various also been an invaluable source of inspir to treat diarrhoea, Ephedra sinica (ephe- compounds and to determine their struc- ation for organic chemists to synthesize dra herb) as an anti-asthmatic and Melia tures, which, in turn, has given insights into novel drug candidates (Beghyn et al, 2008; azedarach (chinaberry seed) as an anti- their action on the human body. In 1805, Hunter, 2008; Koehn & Carter, 2005). Some helmintic. In 659 AD, China issued the first the German pharmacist Friedrich Wilhelm have even claimed that the switch away national pharmacopaeia, Xin Xiu Ben Cao Sertürner (1783–1841) isolated morphine from natural products to combinatorial (Newly Revised Medicinal Materials, also from opium, and it became both the first chemistry during the 1990s might have led called Tang Ben Cao), which contained pure naturally derived medicine and the first to the current paucity of new drug cand 850 agents (Gao, 2004). In 1587 aD, Li to be commercialized, by Merck in 1826. idates in the development pipeline (Desai Shi-Zhen published his famous work Ben In fact, Western pharmaceutical compa- & Chackalamannil, 2008). It is therefore Cao Gang Mu (Compendium of Medicinal nies quickly began to prefer purified nat a matter of great scientific, economic and Materials), which recorded 1,892 agents ural products as ingredients to make drugs, medical interest to analyse and understand and about 11,000 combinatorial formulae rather than crude extracts. In addition, the why so many natural products are beneficial (Gao, 2004). elucidation of the molecular structures to human health. of many natural products allowed chemists to synthesize them, rather than isolating any chemists and biologists have …we need to move beyond either them from natural sources, which markedly attempted to explain the puzzle xenohormesis or co-evolution lowered the cost of drug production. Mof why so many compounds in to explain the biological effects Subsequently, a large number of well- nature have biological effects in humans of natural products known natural compounds were identi- and other species. One explanation that fied, analysed and synthesized: salicin has been widely accepted is that it is the from Salix alba (white willow), emetine result of long-term co-evolution within Although the ancient Occidental and from Cephaelis ipecacuanha (ipecac- biological communities: interacting organ- Oriental medicinal systems developed uanha), strychnine and brucine from isms that evolved in close proximity to independently of one other, it is interest- Strychnos nux-vomica (strychnos), quinine one another developed compounds that ing to note that their respective practition- from Cinchona ledgeriana (cinchona bark), could influence the biological processes ers often used the same natural products colchicine from Colchicum autumale of neighbouring species. As these com- to treat similar diseases. For example, both (colchicum), caffeine from Coffea arabica, pounds proved to be advantageous, they Shen Nong Ben Cao Jing and De Materia nicotine from Nicotiana tabacum, atro- became a trait on which natural selection Medica describe the use of an extract from pine from Atropa belladonna and cocaine could act, and were retained and improved Tussilago farfara as an antitussivum to sup- from Erythroxylum coca. Many of these throughout the course of evolution. Given press coughing. Hippocrates used an extract compounds are still widely used as drugs. the similarities between aspects of human of Veratrum album (white hellebore) as an The twentieth century saw the discovery physiology and that of other animals, it is emetic, whereas his Chinese counterparts of the antibacterial properties of peni not surprising that such molecules can used that of Veratrum nigrum (black helle- cillin, derived from the mould Penicillium also exert biological effects in humans. bore). The oil of Nepeta cataria (catnip) was notatum, which was soon followed by For example, many chemicals that plants used as an antipyretic in Europe for thou- various other antibacterials that gave phys evolved to defend themselves against herb sands of years, and Shen Nong Ben Cao Jing icians an enormously powerful weapon in ivores are now used as laxatives, emetics, notes the same use for another species of the their battle against infectious diseases. cardiotonics or muscle relaxants in humans family, Nepeta tenuifolia. As there seems The structural analysis of natural com- (Briskin, 2000). In addition, humans have to have been little regular communication pounds and the ability to synthesize them taken advantage of some of the discovered between China and Europe 2,000 years ago, allowed chemists to modify them in order properties of natural compounds: those this would seem to be an example of the to suppress or enhance certain character- that are able to interact with or suppress the convergent evolution of different medicinal istics such as solubility, efficiency or stab growth of bacteria, for example, are now systems (Kong et al, 2008a). ility in the human body. Newman (2008) used as antimicrobial drugs in medicine.

A (–)-Huperzine A Physostigmine as 5’-methoxyhydnocarpin (Stermitz et al, 2000). The latter have no microbicidal activity of their own, but seemingly potentiate the antibiotic effects of other molecules. This phenomenon could be explained in terms of co-evolution and the classic ‘arms race’ between host and pathogen. Plants that evolved antimicrobials were able to defend themselves against pathogenic bacteria; pathogens that evolved resistance mecha- Bellidifolin Ursolic acid nisms, such as MDR pumps, were able to break plant defences; in turn, plants that developed MDR inhibitors had a significant evolutionary advantage (Li & Zhang, 2008).

…the popularity of natural products will continue simply because they are a matchless source of novel drug leads and B inspiration for the synthesis of non-natural molecules…

Some compounds exert their biological effects by mimicking endogenous meta bolites, including ligands, hormones or other molecules involved in inter- and intra cellular signal transduction. For example, some alkaloids—such as anagyrine from Anagyris foetida, cytosine from Laburnum anagyroides, lupanine from Cytisus scoparius [Syn. Spartium scoparium] or sparteine from Chelidonium majus—affect neuroreceptors by forming a quaternary nitrogen configur ation that resembles a structural motif present in most neurotransmitters (Wink, 2003). In other cases, different organisms use similar molecules for the same purpose: brassino lids are plant steroid hormones, which reg ulate cell division and cell development in the plant, and that are structurally similar to human growth-regulating steroids.

ecently, Howitz & Sinclair (2008) proposed an alternative hypothesis, Rcalled xenohormesis, to explain Fig 1 | Molecular structures of natural inhibitors of acetylcholinesterase. (A) (–)-Huperzine A the origin of beneficial natural products.

(EC 50 = 0.1 nM), physostigmine (EC 50 = 0.6 nM), bellidifolin (EC 50 = 0.15 nM) and ursolic acid According to their theory, the common

(EC 50 = 7.5 nM). (B) Binding sites of these inhibitors on the acetylcholinesterase. (–)-Huperzine A is ancestor of plants and animals was able to shown in red, physostigmine in yellow, bellidifolin in cyan and ursolic acid in orange. The X-ray structure synthesize a large number of stress-induced of acetylcholinesterase and (–)-huperzine A was obtained from the Protein Data Bank (entry 1VOT). The secondary metabolites. Animals and fungi binding of the other three inhibitors was calculated by using the FlexX module of SYBYL 7.0. that feed on plants gradually lost the capac- ity to synthesize these low-weight molecular compounds, but retained the ability to The co-evolution theory also explains potential of Berberis spp. (Pepperidge sense these chemical cues in plants, pos- other phenomena, including synergistic bush) is caused not only by antimicro- sibly in order to detect when plants were effects. Several years ago, Lewis and co- bial agents such as berberine, but also by stressed and gain an early warning of workers showed that the high antimicrobial multidrug-resistance (MDR) inhibitors such changing environmental conditions.

Asp 964

His 114 AB C Quercetin Quercetin Quercetin

Asn 110 Met 89 Lys 833

Phe 56

Gly 98 Glu 880

Val 882

Fig 2 | Binding modes of quercetin. Binding to (A) phosphatidylinositol-3-kinase; (B) helix–turn–helix-type transcriptional regulator; and (C) 3-hydroxyisobutyryl- CoA hydrolase.

This theory is at least partly supported by ease pain and reduce fever; yet, although in the three-dimensional structures of natural the finding that certain human genes have the effective component is salicylic acid, product–target complexes. homologues in plants and microbes—at willow bark only contains the precursor least to the extent that plants and animals use salicin, which is hydrolysed in the small odern structural biology has made similar signalling molecules and receptors in intestine to salicylic alcohol and further possible the exact determination some cases. Indeed, a comparative genomic oxidized to salicylic acid by intestinal bac- Mof the crystal structures of protein analysis revealed that 70% of cancer- teria (Akao et al, 2002). Another example is target–inhibitor complexes, such as HIV-1 related human genes have orthologues in phenolic glucoside arbutin, which is used to protease–lopinavir complex or AChE– Arabidopsis thaliana ( Jones et al, 2008). Thus, treat urinary tract infections. This compound huperzine A complex. These studies have given the similarity of many plant and human itself is ineffective until it is hydrolysed and revealed that, in most cases, the relation- genes, it seems obvious that some secondary oxidized to hydroquinone in the human ship between a target and a native inhibi- metabolites produced by plants to modulate body. Further examples are the sennosides, tor is not a rigid lock and key combination. their own metabolism should also be able to which are converted into laxative anthrones First, the same macromolecule can bind bind to molecules that have a role in human by bacteria in the gut. Similarly, conjugated to distinct inhibitors. By way of example, disease. For example, multidrug resistance- phytoestrogens have to be hydrolysed in the natural inhibitors of AChE can have differ- like proteins that are used by Arabidopsis to stomach or the gut to exert their oestrogen- ent structures (Fig 1A), but have comparable transport auxin have orthologues in humans like effects (Hostettmann & Marston, 2007). inhibitory activities (Mukhejee et al, 2007). that are crucial for the transport of anti-cancer Strictly speaking, these plant molecules are The explanation for this is that the binding agents; auxin-distribution modulators such not drugs, but proto-drugs. cavity of the protein is larger than the small as flavonoids from Arabidopsis can inhibit inhibitor, which means that there are many P-glycoprotein (MDR1) in various human …natural products provide binding modes for these agents to modify cancer cells (Taylor & Grotewold, 2005). enzyme activity. Fig 1B shows how four important clues for identifying AChE inhibitors are able to occupy different owever, neither theory explains and developing synergistic parts of the protein. the full power of natural products. drugs that, so far, research has Second, many natural compounds can HFirst, some natural compounds— largely neglected bind to diverse proteins. Quercetin, for for example, curcumin, resveratrol or quer- example, can inhibit enzymes with distinct cetin—can bind to many target molecules architectures such as phosphatidylinositol- implicated in human disease (Aggarwal 3-kinase, which has a protein kinase-like & Shishodia, 2006; Goel et al, 2008; Ji & Third, some of the biological effects of fold; helix–turn–helix-type transcriptional Zhang, 2008). Some of these targets such as these natural products—such as slowing regulator, which has a tetracycline repressor- acetylcholinesterase (AChE) or monoamine down the progress of Alzheimer disease or like fold; and 3-hydroxyisobutyryl-CoA oxidases A and B, are unique to animals and dementia—give no obvious advantage to the hydrolase, which has a ClpP/crotonase have no homologues in plants that produce producer of the agent, and so their action can- fold (Fig 2A–C). This phenomenon is likely these natural agents. not be explained as the result of co-evolution. to result from the fact that ligand-binding Second, the health effects of many plant Taken together, these puzzling observations cavities are less diverse than protein arch compounds are not intrinsic to those mol seem to suggest that we need to move beyond itectures ( Ji et al, 2007; McArdle & Quinn ecules but are a consequence of the human either xenohormesis or co-evolution to 2007); that both natural products and pro- digestive system processing their meta explain the biological effects of natural prod- teins are flexible entities, which allows them bolites. Willow bark has long been used to ucts. In turn, this has stimulated our interest to adapt their configuration; and that natural

A ◀ Fig 3 | Binding modes of quercetin and its they are a matchless source of novel Lys 213 Aromadendrin precursors. (A) Aromadendrin with flavanone drug leads and inspiration for the synthe- 3-dioxygenase; (B) taxifolin with flavonoid sis of non-natural molecules (Baker et al, 3',5'-hydroxylase; (C) quercetin with flavonol 2007; Beghyn et al, 2008; Harvey, 2008; Glu 306 synthase. (D) Quercetin (cyan) superimposed Hunter, 2008; Koehn & Carter, 2005). In with aromadendrin (red) and taxifolin (yellow). addition, natural products provide impor- The structures of flavonoid 3',5'-hydroxylase tant clues for identifying and developing and flavonol synthase were modelled based on synergistic drugs that, so far, research has the crystal structures of cytochrome P450 from largely neglected. Most modern drug dis- Val 235 Asp 234 Homo sapiens (similarity: 49%) and anthocyanidin covery has been based on a ‘one-disease– synthase from Arabidopsis thaliana (similarity: one-target–one-drug’ strategy. The patho- 62%) respectively, by using the homology module genesis of many diseases involves multiple of Insight II. factors, however, and a selective com-

B Taxifolin pound against a single target often fails to achieve the desired effect, particularly in cancer therapy. Consequently, there is Pro 435 in the final steps, each of which has distinct increasing interest in ‘multi-component architectures and molecule-binding cavities, therapeutics’ to overcome the challenge and all of which the quercetin molecule of ‘more investment, fewer drugs’ (Keith

Arg 441 under synthesis must be able to interact et al, 2005; Schmidt et al, 2007; Kong with (Fig 3A–C). The core structure of quer- et al, 2008b). This new strategy could have cetin has therefore inherited diverse bind- several advantages as it would modulate Arg 100 ing groups and a certain level of flexibility biological networks rather modestly and in order to be able to bind to these enzymes might therefore be more efficient in deal- C (Fig 3). This diversity and flexibility thus ing with complex diseases (Csermely et al, allows it to interact with other unintended 2005; Dancey & Chen 2006; Zimmermann Asn 217 proteins with similar binding sites. et al, 2007). Moreover, it could prevent, Arg 300 or at least slow down, the development n the early 1990s, many pharmaceutical of resistance against many antibiotics, Quercetin companies concentrated their research antimalarials and anti-cancer drugs. Iefforts on combinatorial chemistry and high-throughput screening to gener- he prospect of new and better drug ate and identify new drug candidates. combinations is enticing, and nat However, this strategic shift did not bring ural compounds hold great promise. His 234 T the expected returns in terms of new drug Nevertheless, a huge challenge remains His 272 candidates. In 2007, only 17 new drug to identify natural compounds—or nat entities were approved, compared with 53 urally inspired compounds—that can be in 1996. Moreover, given the average dur combined to be effective against human His 290 Asp 236 ation of drug discovery and development, disease. The enormous number of possible D most of the latter were originally identified drug combinations, the inherent risks of in the 1980s (Hughes, 2008). Pharmacists harmful drug–drug interactions, the poss and chemists are therefore turning their ible antagonistic effects and the unpre- attention back to nature’s toolbox: indeed, dictable pharmacokinetic properties of some promising drug candidates such as multi-component formulations must still be huperzine A, triptolide, celastrol, cap- addressed. As pointed out above, we have saicin and curcumin, have come from this a rich historical record from ancient phys recent focus on natural agents ( Ji & Zhang, icians about how to use natural medicines 2008; Corson & Crews, 2007). However, it alone and in combination, which might products usually have diversified binding remains an important challenge to find bio- provide important clues for developing groups, a subset of which is sufficient to bind logically active compounds and to develop new drugs (Schmidt et al, 2007; Verpoorte to the target, as explained below. these into new drugs, even if one uses et al, 2009). In fact, the reason why natural products nature for inspiration. Their complex evolu- To make the best use of our forbear- are able to bind to multiple target molecules tionary histories mean that the structures of ers’ knowledge, we need to analyse these might be due to their mode of generation. natural compounds are highly likely to gen- medical formulae and elucidate their syn- Many of the natural compounds used in erate secondary effects and their efficacy ergistic effects. We already know of some medicine have a complex structure and their often depends on synergistic interactions compounds that are more powerful in combi- synthesis involves a range of enzymes. In the with other components (Keith et al, 2005). nation than alone: for example, the combina- case of quercetin biosynthesis, for example, Nonetheless, the popularity of natural tion of Realgar, Indigo naturalis, Radix salviae no less than three synthetases are involved products will continue simply because miltiorrhizae and Radix pseudostellariae

constitutes a formula in TCM that has proven treat diabetes-related cognitive disorders Corson TW, Crews CM (2007) Molecular effective against human acute promyelo- (Kong et al, 2008b). understanding and modern application of traditional medicines: triumphs and trials. Cell cytic leukaemia (Huang et al, 1995). Its syn- These formulae also contain important 130: 769–774 ergistic effect was recently attributed to the clues about synergistic effects that could Csermely P, Agoston V, Pongor S (2005) The direct anti-cancer properties of tetra-arsenic provide new leads for the fight against efficiency of multi-target drugs: the network tetrasulphide from Realgar and the comple- complex diseases such as cancer and approach might help drug design. Trends mentary effects of indirubin and tanshinone dementia. Most of these compounds are Pharmacol Sci 26: 178–182 Dancey JE, Chen HX (2006) Strategies for IIA from Indigo naturalis and Radix salviae available as pure chemicals and some optimizing combinations of molecularly miltiorrhizae, respectively, which enhance have already been used in the clinic for targeted anticancer agents. Nat Rev Drug the transport of tetra-arsenic tetrasulphide into many years. This accumulated experience Discov 5: 649–659 target cells and thus potentiates its efficacy from TCM and other ancient medicinal Desai MC, Chackalamannil S (2008) Rediscovering the role of natural products in (Wang et al, 2008). practices could allow modern researchers drug discovery. Curr Opin Drug Discov Devel to design and control synergistic effects far 11: 436–437 …we have a rich historical record better than was possible by blending crude Dev S (1999) Ancient–modern concordance in natural products. Ayurvedic plants: some examples. Environ from ancient physicians […], As mentioned above, a strategy to ana- Health Perspect 107: 783–789 Gao XM (2004) Advanced Traditional Chinese which might provide important lyse and modify synergistic drug combin Medicine Series/ Chinese Materia Medica clues for developing new drugs… ations still poses considerable challenges (Volume 1). Beijing, China: People’s Medical for research, clinical development and Publishing House regulatory agencies. Nonetheless, mod- Goel A, Kunnumakkara AB, Aggarwal BB (2008) Curcumin as “Curecumin”: from kitchen to Similarly, the combination of Coptidis ern pharmaceutical research, using the clinic. Biochem Pharmacol 75: 787–809 rhizoma and Evodia rutaecarpa, known as powerful tools of genomics, proteomics, Harvey AL (2008) Natural products in drug Zuo Jin Wan, has been used for more than metabolomics and synthetic and combin discovery. Drug Discov Today 13: 894–901 700 years in TCM to treat gastric cond atorial chemistry, could learn a lot from the Hostettmann K, Marston A (2007) The search for itions. This herbal combination contains historical record of using natural products new drugs from higher plants. CHIMIA: Int J Chem 61: 322–326 possible drug candidates such as berberine to fight diseases—after all, this knowledge Howitz KT, Sinclair DA (2008) Xenohormesis: and calystigine—antibiotics and poten- represents the cumulative experience of sensing the chemical cues of other species. Cell tial inhibitors of Helicobacter pylori— thousands of years of medical practice. 133: 387–391 limonene, an antineoplastic agent, and Huang SL, Guo AX, Xiang Y, Wand XB, Lin HX, ACKNOWLEDGEMENTS Fu L (1995) Clinical study on the treatment of obacunone and rutecarpine, which are acute promyelocytic leukemia with composite inhibitors of cancer-cell multidrug resist- This study was supported by the National Basic Research Program of China (2003CB114400), the Indigo naturalis tablets. Chin J Hematol 16: ance, which are all relevant to treating 26–28 National Natural Science Foundation of China Hughes B (2008) 2007 FDA drug approvals: a gastric conditions including cancers (Kong (30870520 and 30700113) and Outstanding et al, 2008c). Thus, this naturally occurring, year of flux. Nat Rev Drug Discov 7: Youth Foundation of Shandong Province 107–109 effective combination of chemicals points ( JQ200812). 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