《生物技术与人类》课程教学资源（经典阅读）Plant natural products Back to the future or into extinction

Available online at www.sciencedirect.com ScienceDirect PHYTOCHEMISTRY ELSEVIER Phytochemistry 68(2007)2015-2022 www.elsevier.com/locate/phytochem Plant natural products:Back to the future or into extinction? James D.McChesney a.b.",Sylesh K.Venkataraman a,John T.Henri a Tapestry Pharmaceuticals.Inc..4840 Pearl East Cir.#300W.Boulder.CO80301.United States ChromaDex Analytics,Inc.,2830 Wilderness Place,Boulder,CO 80301.United States Received 20 December 2006;received in revised form 23 March 2007 Abstract Natural product substances have historically served as the most significant source of new leads for pharmaceutical development. However,with the advent of robotics,bioinformatics,high throughput screening(HTS),molecular biology-biotechnology,combinato- rial chemistry,in silico(molecular modeling)and other methodologies,the pharmaceutical industry has largely moved away from plant derived natural products as a source for leads and prospective drug candidates.Can,or will,natural products ever recapture the preem- inent position they once held as a foundation for drug discovery and development?The challenges associated with development of nat- ural products as pharmaceuticals are illustrated by the Taxol story.Several misconceptions,which constrain utilization of plant natural products,for discovery and development of pharmaceuticals,are addressed to return natural products to the forefront. 2007 Elsevier Ltd.All rights reserved. Keywords:Plant natural products;Drug discovery:Agronomic production;Biomass 1.Introduction icant sources of drugs and leads.Their dominant role is evi- dent in the approximately 60%of anticancer compounds Natural products have been investigated and utilized to and 75%of drugs for infectious diseases that are either nat- alleviate disease since early human history.In the early ural products or natural product derivatives (Newman 1900s,before the "Synthetic Era",80%of all medicines et al.,2003;Cragg et al.,2005).Despite this success,during were obtained from roots,barks and leaves.At that time, the past couple of decades,research into natural products fluid extracts were in vogue.One pound of a crude botan- has experienced a steady global decline.The introduction ical was percolated with a pint of alcohol,much as we of high-throughput synthesis and combinatorial chemistry make coffee today."Take a teaspoonful of this before with their promise of a seemingly inexhaustible supply of meals",the family doctor would say,perhaps adding that compound libraries has greatly contributed to this declin- a mustard plaster or vegetable poultice would do no harm. ing interest in the screening of natural products by the Every household had its favorite tea and tonics.Trustful pharmaceutical industry. humanity placed its faith in the belief that for every ill there existed a cure in the plants of field and forest.As Rudyard Kipling wrote(1910),"Anything green that grew out of the 2.Discovery and development from natural products mould was an excellent herb to our fathers of old."In more recent times,natural products have continued to be signif- Some of the opportunities for natural products'discov- ery and development are in pharmaceuticals,agrochemi- Corresponding author.Address:Tapestry Pharmaceuticals,Inc.4840 cals,cosmetics,fine chemicals and nutraceuticals.The Pearl East Cir.#300W,Boulder,CO 80301,United States.Tel.:+1 303 requirements for discovery,development and commerciali- 5168500:fax:+13035301296. zation of pharmaceuticals are generally well known.The E-mail address:jmcchesney@tapestrypharma.com (J.D.McChesney). time required for development of pharmaceuticals ranges 0031-9422/S-see front matter 2007 Elsevier Ltd.All rights reserved. doi:10.1016/j.phytochem.2007.04.032

Plant natural products: Back to the future or into extinction? James D. McChesney a,b,*, Sylesh K. Venkataraman a , John T. Henri a a Tapestry Pharmaceuticals, Inc., 4840 Pearl East Cir. #300W, Boulder, CO 80301, United States b ChromaDex Analytics, Inc., 2830 Wilderness Place, Boulder, CO 80301, United States Received 20 December 2006; received in revised form 23 March 2007 Abstract Natural product substances have historically served as the most significant source of new leads for pharmaceutical development. However, with the advent of robotics, bioinformatics, high throughput screening (HTS), molecular biology-biotechnology, combinato￾rial chemistry, in silico (molecular modeling) and other methodologies, the pharmaceutical industry has largely moved away from plant derived natural products as a source for leads and prospective drug candidates. Can, or will, natural products ever recapture the preem￾inent position they once held as a foundation for drug discovery and development? The challenges associated with development of nat￾ural products as pharmaceuticals are illustrated by the Taxol story. Several misconceptions, which constrain utilization of plant natural products, for discovery and development of pharmaceuticals, are addressed to return natural products to the forefront. 2007 Elsevier Ltd. All rights reserved. Keywords: Plant natural products; Drug discovery; Agronomic production; Biomass 1. Introduction Natural products have been investigated and utilized to alleviate disease since early human history. In the early 1900s, before the ‘‘Synthetic Era’’, 80% of all medicines were obtained from roots, barks and leaves. At that time, fluid extracts were in vogue. One pound of a crude botan￾ical was percolated with a pint of alcohol, much as we make coffee today. ‘‘Take a teaspoonful of this before meals’’, the family doctor would say, perhaps adding that a mustard plaster or vegetable poultice would do no harm. Every household had its favorite tea and tonics. Trustful humanity placed its faith in the belief that for every ill there existed a cure in the plants of field and forest. As Rudyard Kipling wrote (1910), ‘‘Anything green that grew out of the mould was an excellent herb to our fathers of old.’’ In more recent times, natural products have continued to be signif￾icant sources of drugs and leads. Their dominant role is evi￾dent in the approximately 60% of anticancer compounds and 75% of drugs for infectious diseases that are either nat￾ural products or natural product derivatives (Newman et al., 2003; Cragg et al., 2005). Despite this success, during the past couple of decades, research into natural products has experienced a steady global decline. The introduction of high-throughput synthesis and combinatorial chemistry with their promise of a seemingly inexhaustible supply of compound libraries has greatly contributed to this declin￾ing interest in the screening of natural products by the pharmaceutical industry. 2. Discovery and development from natural products Some of the opportunities for natural products’ discov￾ery and development are in pharmaceuticals, agrochemi￾cals, cosmetics, fine chemicals and nutraceuticals. The requirements for discovery, development and commerciali￾zation of pharmaceuticals are generally well known. The time required for development of pharmaceuticals ranges 0031-9422/$ - see front matter 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.phytochem.2007.04.032 * Corresponding author. Address: Tapestry Pharmaceuticals, Inc., 4840 Pearl East Cir. #300W, Boulder, CO 80301, United States. Tel.: +1 303 516 8500; fax: +1 303 530 1296. E-mail address: jmcchesney@tapestrypharma.com (J.D. McChesney). www.elsevier.com/locate/phytochem Phytochemistry 68 (2007) 2015–2022 PHYTOCHEMISTRY

2016 J.D.McChesney et al.Phytochemistry 68 (2007)2015-2022 Usual Range of Approximate Time Required Mean Time (years) Required (years) Stage of Development 1.Project Formation to IND Filing 1.5to3.5 2.5 BzO H 2.Phase I Clinical Studies 0.5to1.5 1.0 OAc 3.Phase II Clinical Studies 1.0to5.0 3.0 Fig.1.Structure of paclitaxel (1) 4.Phase III Clinical Studies and 1.0to5.0 3.0 Preparation of NDA from a few years to as many as 20 years.For example,the FDA Review of NDA 1.0to5.0 2.5 chemical structure of paclitaxel (1)(Taxol )(Fig.1)was reported and identified as the cytotoxic active constituent Totals 5.0to20.0 12.0 of extracts of Taxus brevifolia in 1971 (Wani et al.,1971). Taxol (1)was approved for marketing as a cancer chemo- Fig.3.Typical time requirements to develop new drugs. therapeutic agent at the end of 1992,20 years later.On average,new pharmaceuticals require a decade for devel- of new pharmaceuticals.The challenges must be identified opment and commercialization.This timeframe has not and addressed if we are to return natural products to their changed appreciably in the last quarter century.The time- preeminent position as the foundation of new pharmaceu- line for those activities are outlined in Fig.2(Tapestry tical discovery and development. Pharmaceuticals,2006)and the length of each of the vari- ous phases are recorded in Fig.3(Basara and Montagne, 1994). 3.Biodiversity and natural products It is interesting that as information on the development of natural products is gathered,discussion of many of the Pharmaceutical discovery is a numbers game.Thou- important issues relative to natural products development sands of chemicals must be evaluated to find a hit.The is not found.Nowhere in this timeline is consideration interesting agents that are identified as natural products given to supplying the quantity of drug needed for develop- derive from the phenomenon of biodiversity,i.e.,the rich- ment,nor to developing a supply for commercial market- ness in variety of organisms in the ecosphere.A conse- ing.Those can be very challenging issues and are,we quence of the interaction of this rich variety of organisms believe,the primary constraints on development of natural with each other and their environment is the evolution of products as pharmaceuticals.These challenges are often diverse complex natural chemicals in the organisms that viewed by pharmaceutical company executives as too limit- enhance their survival and competitiveness (Waterman. ing for the utilization of natural products(especially plant- 1992).There are literally millions of natural chemical struc- derived natural products)for discovery and development ture types resulting from nature's combinational chemistry PRE-CLINICAL CLINICAL STUDIES NDA REVIEW RESEARCH Phase E Phase 2 SYNTHESIS AND PURIFICATION Phase 3 ANIMAL Accelerated Development/Review TESTING Short-Term Long-Term DD Submitted INSTITUTIONAL Review REVIEW BOARDS NDA Submitted Sponsor/FDA meetings encouraged SubpartE Decision Sponsor answers any Advisory Committees questions from review Fig.2.Timeline for new-drug development

from a few years to as many as 20 years. For example, the chemical structure of paclitaxel (1) (Taxol) (Fig. 1) was reported and identified as the cytotoxic active constituent of extracts of Taxus brevifolia in 1971 (Wani et al., 1971). Taxol (1) was approved for marketing as a cancer chemo￾therapeutic agent at the end of 1992, 20 years later. On average, new pharmaceuticals require a decade for devel￾opment and commercialization. This timeframe has not changed appreciably in the last quarter century. The time￾line for those activities are outlined in Fig. 2 (Tapestry Pharmaceuticals, 2006) and the length of each of the vari￾ous phases are recorded in Fig. 3 (Basara and Montagne, 1994). It is interesting that as information on the development of natural products is gathered, discussion of many of the important issues relative to natural products development is not found. Nowhere in this timeline is consideration given to supplying the quantity of drug needed for develop￾ment, nor to developing a supply for commercial market￾ing. Those can be very challenging issues and are, we believe, the primary constraints on development of natural products as pharmaceuticals. These challenges are often viewed by pharmaceutical company executives as too limit￾ing for the utilization of natural products (especially plant￾derived natural products) for discovery and development of new pharmaceuticals. The challenges must be identified and addressed if we are to return natural products to their preeminent position as the foundation of new pharmaceu￾tical discovery and development. 3. Biodiversity and natural products Pharmaceutical discovery is a numbers game. Thou￾sands of chemicals must be evaluated to find a hit. The interesting agents that are identified as natural products derive from the phenomenon of biodiversity, i.e., the rich￾ness in variety of organisms in the ecosphere. A conse￾quence of the interaction of this rich variety of organisms with each other and their environment is the evolution of diverse complex natural chemicals in the organisms that enhance their survival and competitiveness (Waterman, 1992). There are literally millions of natural chemical struc￾ture types resulting from nature’s combinational chemistry O AcO O OH O H OAc BzO HO Ph NH OH O O Ph Fig. 1. Structure of paclitaxel (1). Fig. 2. Timeline for new-drug development. Usual Range of Time Required (years) Approximate Mean Time Required (years) Stage of Development 1. Project Formation to IND Filing 1.5 to 3.5 2.5 2. Phase I Clinical Studies 0.5 to 1.5 1.0 3. Phase II Clinical Studies 1.0 to 5.0 3.0 4. Phase III Clinical Studies and Preparation of NDA 1.0 to 5.0 3.0 5. FDA Review of NDA 1.0 to 5.0 2.5 Totals 5.0 to 20.0 12.0 Fig. 3. Typical time requirements to develop new drugs. 2016 J.D. McChesney et al. / Phytochemistry 68 (2007) 2015–2022

J.D.McChesney et al.Phytochemistry 68 (2007)2015-2022 2017 effort supplying almost unimaginable chemical diversity, stability may be marginal;they may have poor solubility which yields stereochemically complex structures with or poor bioavailability characteristics;they may not formu- diverse functional groups,molecules ideal for interacting late well,etc.,therefore not adhering to Lipinski's Rule of specifically with biological target molecules.Importantly, Five (Lipinski et al.,1997).All of these issues have posed nature has been"doing"combinational chemistry for eons, serious challenges.In our judgment,the issue most respon- not just a decade or two,and has been selecting products sible for limited interest in plant derived natural products from that combinational library that have specific biologi- for pharmaceutical discovery and development has been cal advantage.Natural products researchers have not concern over the availability of quantities of pure chemical aggressively promoted natural product preparations in substances.Quantities are required initially for generation terms of nature's remarkable combinational chemistry of information to understand and assess real potential of numbers game.As Aristotle said,"Nature does nothing the substance for pharmaceutical application.Ultimately, without purpose or uselessly." the most limiting consideration is the quantity required to meet market demand should a pharmaceutical become a successful drug in the market place.Market demand 4.Historic role of natural products in discovery of new can reach a scale of hundreds to thousands of kilograms pharmaceuticals per annum.It is recognized that total synthesis will not eco- nomically provide the complex natural product to meet this Natural product preparations have historically been the market demand.We believe the problems mentioned above major source of pharmaceutical agents.Analysis of FDA can be overcome new-drug approvals from 1981 to 2002 reveals that natural products continued to play a pivotal role during that time, even if the industry had turned to other discovery strategies 5.The renaissance in natural products research (Newman et al.,2003).Indeed,more than 90%of current therapeutic classes derive from a natural product prototype Natural products have pointed the way to the future. and interestingly,even today,roughly two-thirds to three- Many significant advances in science and industry have quarters of the world's population relies upon medicinal been inspired by the pursuit of capturing the value of nat- plants for its primary pharmaceutical care(World Health ural products.Testaments to the role natural products have Organization,2002).Those "medicinal plants"are either played in the evolution of organic synthesis are in Classics preparations of or natural product substances from plants In Total Synthesis (Nicolaou and Sorenson,1996)and that have potential utility as pharmaceutical agents (Bal- Classics in Total Synthesis II (Nicolaou and Snyder. unas and Kinghorn,2005). 2003)where all the synthetic targets are natural products. Historically also there were several problems associated Efforts toward total synthesis of natural products have with natural products (especially plant-derived products) resulted in development of new synthetic methods(Wilson that contributed to declining interest in their development and Danishefsky,2006),advances in the fields of medicinal within the pharmaceutical industry.Some years ago,there chemistry,process chemistry and other aspects of the sci- were significant difficulties with sourcing authenticated ence of drug development and,of course,with provision plant materials.It was easy to collect plants and demon- of a continuous and reliable supply of new drugs to the strate that their extracts had interesting biological poten- pharmaceutical industry (Newman et al.,2003;Koehn, tial.However,when researchers returned to confirm the 2005;Ortholand and Ganesan,2004;Paterson and Ander- potential and ultimately to carry out the development son,2005).A number of advances in capability and tech- and commercialization of the product,failure often nology are fostering a renaissance in natural products resulted because of inadequate documentation and loss of research and are directly or indirectly addressing the histor- the original plant collections.There were also problems ical impediments to development of natural products associated with the measurement of biological activities (Brown and Newman,2006;Fullbeck et al.,2006;Gomord of natural product preparations,which ordinarily are com- et al.,2005;Jung,2006;Koehn,2005;Newman,2006; plex mixtures of materials.Interactions among the compo- Schuster,2001;Tulp,2004). nents of the mixtures,either the antagonism by one Perhaps the strongest impetus for development of new material of another's activity or the addition or even syn- natural products is the advancement in bioassay technol- ergy of activities,often gave very misleading results.Purifi- ogy over the last several years (Littleton et al.,2005;Pig- cation and identification of active constituents from got,2004;Potterat,2006;Rollinger et al.,2006).We now complex natural product mixtures containing dozens to have highly automated,very specific and selective bioas- hundreds of different chemical substances,often of quite says in which materials,including natural products prepa- similar chemical and physical properties,were slow and rations,can be evaluated quickly and economically. not cost-effective.Once the active constituent was isolated Indeed,advances in bioassay technology have been so great and purified,its chemical structure still needed to be estab- that the availability of substances for evaluation has lished.These issues are compounded in that natural prod- become more limiting than the ability to carry out those ucts are often poor pharmaceuticals;their chemical evaluations.Once biological activity has been demon-

effort supplying almost unimaginable chemical diversity, which yields stereochemically complex structures with diverse functional groups, molecules ideal for interacting specifically with biological target molecules. Importantly, nature has been ‘‘doing’’ combinational chemistry for eons, not just a decade or two, and has been selecting products from that combinational library that have specific biologi￾cal advantage. Natural products researchers have not aggressively promoted natural product preparations in terms of nature’s remarkable combinational chemistry numbers game. As Aristotle said, ‘‘Nature does nothing without purpose or uselessly.’’ 4. Historic role of natural products in discovery of new pharmaceuticals Natural product preparations have historically been the major source of pharmaceutical agents. Analysis of FDA new-drug approvals from 1981 to 2002 reveals that natural products continued to play a pivotal role during that time, even if the industry had turned to other discovery strategies (Newman et al., 2003). Indeed, more than 90% of current therapeutic classes derive from a natural product prototype and interestingly, even today, roughly two-thirds to three￾quarters of the world’s population relies upon medicinal plants for its primary pharmaceutical care (World Health Organization, 2002). Those ‘‘medicinal plants’’ are either preparations of or natural product substances from plants that have potential utility as pharmaceutical agents (Bal￾unas and Kinghorn, 2005). Historically also there were several problems associated with natural products (especially plant-derived products) that contributed to declining interest in their development within the pharmaceutical industry. Some years ago, there were significant difficulties with sourcing authenticated plant materials. It was easy to collect plants and demon￾strate that their extracts had interesting biological poten￾tial. However, when researchers returned to confirm the potential and ultimately to carry out the development and commercialization of the product, failure often resulted because of inadequate documentation and loss of the original plant collections. There were also problems associated with the measurement of biological activities of natural product preparations, which ordinarily are com￾plex mixtures of materials. Interactions among the compo￾nents of the mixtures, either the antagonism by one material of another’s activity or the addition or even syn￾ergy of activities, often gave very misleading results. Purifi- cation and identification of active constituents from complex natural product mixtures containing dozens to hundreds of different chemical substances, often of quite similar chemical and physical properties, were slow and not cost-effective. Once the active constituent was isolated and purified, its chemical structure still needed to be estab￾lished. These issues are compounded in that natural prod￾ucts are often poor pharmaceuticals; their chemical stability may be marginal; they may have poor solubility or poor bioavailability characteristics; they may not formu￾late well, etc., therefore not adhering to Lipinski’s Rule of Five (Lipinski et al., 1997). All of these issues have posed serious challenges. In our judgment, the issue most respon￾sible for limited interest in plant derived natural products for pharmaceutical discovery and development has been concern over the availability of quantities of pure chemical substances. Quantities are required initially for generation of information to understand and assess real potential of the substance for pharmaceutical application. Ultimately, the most limiting consideration is the quantity required to meet market demand should a pharmaceutical become a successful drug in the market place. Market demand can reach a scale of hundreds to thousands of kilograms per annum. It is recognized that total synthesis will not eco￾nomically provide the complex natural product to meet this market demand. We believe the problems mentioned above can be overcome. 5. The renaissance in natural products research Natural products have pointed the way to the future. Many significant advances in science and industry have been inspired by the pursuit of capturing the value of nat￾ural products. Testaments to the role natural products have played in the evolution of organic synthesis are in Classics In Total Synthesis (Nicolaou and Sorenson, 1996) and Classics in Total Synthesis II (Nicolaou and Snyder, 2003) where all the synthetic targets are natural products. Efforts toward total synthesis of natural products have resulted in development of new synthetic methods (Wilson and Danishefsky, 2006), advances in the fields of medicinal chemistry, process chemistry and other aspects of the sci￾ence of drug development and, of course, with provision of a continuous and reliable supply of new drugs to the pharmaceutical industry (Newman et al., 2003; Koehn, 2005; Ortholand and Ganesan, 2004; Paterson and Ander￾son, 2005). A number of advances in capability and tech￾nology are fostering a renaissance in natural products research and are directly or indirectly addressing the histor￾ical impediments to development of natural products (Brown and Newman, 2006; Fullbeck et al., 2006; Gomord et al., 2005; Jung, 2006; Koehn, 2005; Newman, 2006; Schuster, 2001; Tulp, 2004). Perhaps the strongest impetus for development of new natural products is the advancement in bioassay technol￾ogy over the last several years (Littleton et al., 2005; Pig￾got, 2004; Potterat, 2006; Rollinger et al., 2006). We now have highly automated, very specific and selective bioas￾says in which materials, including natural products prepa￾rations, can be evaluated quickly and economically. Indeed, advances in bioassay technology have been so great that the availability of substances for evaluation has become more limiting than the ability to carry out those evaluations. Once biological activity has been demon￾J.D. McChesney et al. / Phytochemistry 68 (2007) 2015–2022 2017

2018 J.D.McChesney et al Phytochemistry 68 (2007)2015-2022 strated in an appropriate bioassay or primary screen,we an important industrial leader worldwide.The recognition now have available,based upon advances in separations that through the discovery and development of new phar- and structure elucidation technology,the capability to iso- maceuticals the competitive position of that industry can late,purify and determine the chemical structure of the be maintained,leads to interest in natural products active constituent in a few days or,at most,a few weeks. research as a way to increase the efficiency of discovery The advances in separations technology are particularly and development (Vuorela,2004). associated with high performance chromatography meth- odologies(Foucault,1995).Most recently,improved meth- odologies in countercurrent partition chromatography 6.The utilization of the world's plants have further expanded the capabilities for separations(Ber- thod,2002;Pauli,2006).Structure elucidation technology It is generally estimated that there are approximately has evolved particularly with the development of high field 300,000 species of higher plants (Lawrence,1951).How- NMR spectrometry (Croasmun and Carlson,1994;Cla- ever,some report the number to be 250,000,others esti- ridge,1999)as well as high-resolution technologies in mass mate the number to be as high as 500,000.The disparity spectrometry (Deng and Sanyal,2006;Korfmacher,2005). in the numbers partly reflects a difference in philosophy Most important are the two-dimensional NMR techniques among systematic botanists.It also reflects the more that have been developed,which allow very rapid and aggressive exploration of unusual environments,particu- straightforward assignment of structure to complex natural larly diverse environments such as the tropical rainforests, products.Additionally,the technologies of coupled liquid where new species of higher plants are being encountered chromatography-mass spectrometry and similar tech- continually.Of the approximately 300,000 species of higher niques provide very potent and powerful methodologies plants,about 1%,or roughly 3000,has been utilized for for separation and structure elucidation (de Rijke et al., food.Of those 3000.about 150 have been commercially 2006;Niessen,.1999:Gross,2006). cultivated.In today's marketplaces throughout the world, As increased understanding of biological and physiolog- unusual fruits and vegetables are beginning to appear ical pathways in all organisms is reached,much more spe- because there is an increasing desire on the part of the cific and selective questions with regard to potential drug world's populations for more "exotic"foodstuffs.How- application can be formulated.An example of this is the ever,the vast majority of caloric intake derives from about investigation of substances that interact only with a very 20 species of plants.These plants represent the basis upon specific receptor rather than with a family of receptors. which the world's population is fed,representing a very With the advances that have been made in biotechnology, narrow foundation supporting the world's human those receptors can be cloned and "constructs"'prepared population. in which cloned receptors become a component of a cre- On the other hand,approximately 10,000 of the world's ated cell line,which then ultimately forms the basis of a plants have documented medicinal use-considerably more high throughput,very selective and specific bioassay.In than the 3000 or so that have been utilized for food.Look- this way,the advances in several areas can be used together ing specifically at the utilization of plant materials in wes- to focus on the discovery of new substances as lead com- tern medicine (the US,Western Europe,etc.),it is found pounds for pharmaceutical development.Natural products that roughly 150-200 of such agents are incorporated.This represent the most important source of unique chemical is still a very small percentage of all higher plants.Thus, substances for evaluation with these new assaying strate- there are potentially many more important discoveries in gies for potential pharmaceutical utility. the plant kingdom to be exploited for pharmaceutical Recognition that the biological diversity of the earth is application. rapidly diminishing also is fostering a renewal of interest in natural products research.Indeed,we cannot pick up a newspaper or news journal without encountering some 7.The perception that most limits interest in natural products article dealing with the rate,consequences,cause,etc.,of loss of biological diversity.However,it must be empha- Concern over the availability of the quantity of a chem- sized that it is the loss of chemical diversity represented ical entity required for development and market needs,has by those organisms that represents the true loss-the loss been the one most limiting factor for the pharmaceutical of possible benefit that those chemicals have for human- industry's interest in natural products.A realistic assess- kind.Even foodstuffs,building materials,fibers that are ment of quantities of plant material required for the prep- utilized to make clothing,etc.,are chemicals derived from aration of the amount of chemical substance necessary for nature.The loss of those organisms and,in turn,the loss the entire development process will address this concern. of the chemical diversity represented by those organisms, To begin this assessment a"'worst-case scenario must is a very important stimulus for natural products research be assumed.Under this scenario,the presence of an active Additionally,globalization of the world's economy product would be at a concentration of only 0.001%of dry serves as a stimulant for pharmaceutical development. weight of biomass.Current technologies are capable of The US pharmaceutical industry,at the moment,is still identifying potential utility in the bioassay and of isolation

strated in an appropriate bioassay or primary screen, we now have available, based upon advances in separations and structure elucidation technology, the capability to iso￾late, purify and determine the chemical structure of the active constituent in a few days or, at most, a few weeks. The advances in separations technology are particularly associated with high performance chromatography meth￾odologies (Foucault, 1995). Most recently, improved meth￾odologies in countercurrent partition chromatography have further expanded the capabilities for separations (Ber￾thod, 2002; Pauli, 2006). Structure elucidation technology has evolved particularly with the development of high field NMR spectrometry (Croasmun and Carlson, 1994; Cla￾ridge, 1999) as well as high-resolution technologies in mass spectrometry (Deng and Sanyal, 2006; Korfmacher, 2005). Most important are the two-dimensional NMR techniques that have been developed, which allow very rapid and straightforward assignment of structure to complex natural products. Additionally, the technologies of coupled liquid chromatography–mass spectrometry and similar tech￾niques provide very potent and powerful methodologies for separation and structure elucidation (de Rijke et al., 2006; Niessen, 1999; Gross, 2006). As increased understanding of biological and physiolog￾ical pathways in all organisms is reached, much more spe￾cific and selective questions with regard to potential drug application can be formulated. An example of this is the investigation of substances that interact only with a very specific receptor rather than with a family of receptors. With the advances that have been made in biotechnology, those receptors can be cloned and ‘‘constructs’’ prepared in which cloned receptors become a component of a cre￾ated cell line, which then ultimately forms the basis of a high throughput, very selective and specific bioassay. In this way, the advances in several areas can be used together to focus on the discovery of new substances as lead com￾pounds for pharmaceutical development. Natural products represent the most important source of unique chemical substances for evaluation with these new assaying strate￾gies for potential pharmaceutical utility. Recognition that the biological diversity of the earth is rapidly diminishing also is fostering a renewal of interest in natural products research. Indeed, we cannot pick up a newspaper or news journal without encountering some article dealing with the rate, consequences, cause, etc., of loss of biological diversity. However, it must be empha￾sized that it is the loss of chemical diversity represented by those organisms that represents the true loss – the loss of possible benefit that those chemicals have for human￾kind. Even foodstuffs, building materials, fibers that are utilized to make clothing, etc., are chemicals derived from nature. The loss of those organisms and, in turn, the loss of the chemical diversity represented by those organisms, is a very important stimulus for natural products research. Additionally, globalization of the world’s economy serves as a stimulant for pharmaceutical development. The US pharmaceutical industry, at the moment, is still an important industrial leader worldwide. The recognition that through the discovery and development of new phar￾maceuticals the competitive position of that industry can be maintained, leads to interest in natural products research as a way to increase the efficiency of discovery and development (Vuorela, 2004). 6. The utilization of the world’s plants It is generally estimated that there are approximately 300,000 species of higher plants (Lawrence, 1951). How￾ever, some report the number to be 250,000, others esti￾mate the number to be as high as 500,000. The disparity in the numbers partly reflects a difference in philosophy among systematic botanists. It also reflects the more aggressive exploration of unusual environments, particu￾larly diverse environments such as the tropical rainforests, where new species of higher plants are being encountered continually. Of the approximately 300,000 species of higher plants, about 1%, or roughly 3000, has been utilized for food. Of those 3000, about 150 have been commercially cultivated. In today’s marketplaces throughout the world, unusual fruits and vegetables are beginning to appear because there is an increasing desire on the part of the world’s populations for more ‘‘exotic’’ foodstuffs. How￾ever, the vast majority of caloric intake derives from about 20 species of plants. These plants represent the basis upon which the world’s population is fed, representing a very narrow foundation supporting the world’s human population. On the other hand, approximately 10,000 of the world’s plants have documented medicinal use – considerably more than the 3000 or so that have been utilized for food. Look￾ing specifically at the utilization of plant materials in wes￾tern medicine (the US, Western Europe, etc.), it is found that roughly 150–200 of such agents are incorporated. This is still a very small percentage of all higher plants. Thus, there are potentially many more important discoveries in the plant kingdom to be exploited for pharmaceutical application. 7. The perception that most limits interest in natural products Concern over the availability of the quantity of a chem￾ical entity required for development and market needs, has been the one most limiting factor for the pharmaceutical industry’s interest in natural products. A realistic assess￾ment of quantities of plant material required for the prep￾aration of the amount of chemical substance necessary for the entire development process will address this concern. To begin this assessment a ‘‘worst-case’’ scenario must be assumed. Under this scenario, the presence of an active product would be at a concentration of only 0.001% of dry weight of biomass. Current technologies are capable of identifying potential utility in the bioassay and of isolation 2018 J.D. McChesney et al. / Phytochemistry 68 (2007) 2015–2022

J.D.McChesney et al.Phytochemistry 68 (2007)2015-2022 2019 and characterization of the natural product that occurs in However,considering this amount in the context of plant biomass at this low concentration.Identification of crop-based commodities,something that is more easily biological activity,isolation of active product and determi- understood,this represents roughly 2200 tons of biomass, nation of chemical structure require at most 50 mg of the which is the equivalent of about 75,000 bushels of wheat. chemical substance (Cremin and Zeng,2002;Eldridge corn,soybeans or any other commodity.An average Amer- et al.,2002).Isolation of this amount of chemical substance ican farmer produces roughly this 75,000-bushel quantity requires about 5 kg of dry plant material.At this point, or more each year.In this context,we are not talking about with the chemical substance isolated and characterized chopping down and processing entire tropical rainforests and its biological properties determined,a decision point to obtain the 2x 10 kg or more per year of dry plant is reached:Is the chemical structure novel?Does this sub- biomass. stance represent a potential new prototype?If the answers Let us consider another scenario,where the agent is used to these questions are"yes",we now have a natural prod- to treat a chronic condition,the patient population is con- uct hit,and must decide whether to carry it forward into siderably larger-100,000 patients per year,and the agent development. has reasonable potency so that only ca.50 mg per patient Proceeding to the next step means assessing the real per day is required to treat the condition.Under these con- potential of the substance.Confirmatory bioassays must ditions,2000 kg of bulk active drug would be required to be carried out to make sure that the suspected biological meet the market need.Again assuming the "worst-case" activity is actually present.These must be followed with scenario of 0.001%of active product isolated from bio- secondary biological assays to gain a full understanding mass,2x 108 kg of biomass(dry weight)would be required of the breadth and selectivity of the biological activity to produce this 2000 kg per year of bulk active substance. and preliminary toxicology tests (if it cures a particular The number,2x 108 kg,appears to be very large,but when disease but kills the patient,then it is not really likely placed again in the context of crop-based commodities to be a drug substance).Once all of that information is such as wheat or corn or soybeans,it is obvious that this available,some initial in vivo evaluation must be carried represents a modest production level.Indeed,many agri- out to determine that the agent has real promise both cultural counties of the United States produce as much in terms of its efficacy and its toxicity in a "real world" or more than the 7.5 x 10 bushels of a commodity that situation.To carry out these assessments,approximately the 2x 108 kg represent.In this context it is clear that this 400-500 mg of pure active chemical substance is needed. quantity of biomass is readily obtainable. That represents a 10-fold increase in the plant material Two deliberately selected examples emphasize this point. required:as much as 100 kg of biomass (dry weight)is Information on the worldwide production of marijuana needed for processing to gain this additional information. and cocaine leads to the following observations:In 1996, This requirement is not particularly daunting,and it is an estimated 11,000 metric tons were produced worldwide very probable that development would proceed to this with much of that produced in the United States (Gold- stage. berg,2005).At a price of less than $2000 per pound,and Success at this stage would suggest,then,that the agent considering all of the criminal penalties that would ensue would be carried forward into preclinical evaluation.This if one were convicted of producing marijuana,it is clear is where the quantity of dry biomass begins to look like a that,when there is a market for a plant biomass,there will very daunting proposition.The quantity of pure chemical be an entrepreneurial effort to meet that market.Indeed. substance required for full preclinical development and a considering the billions of dollars spent each year to sup- subsequent clinical trial is roughly 2 kg of pure product. press drug plant production,it is easily appreciated that Therefore,in the "worst-case"scenario for active product, giving growers an alternate profitable and ethical crop to (isolation yield from biomass of only 0.001%)200.000 kg of raise,will lead readily to the production of the necessary dry plant biomass would be required to produce the quantities of biomass for drug production to meet pharma- required pure active product to this point. ceutical application.In the case of cocaine,which is utilized Next,should the substance be carried forward through as a nearly pure chemical entity (about $18,000 per kg at development and demonstrated to have true pharmaceuti- source)indeed a thousand tons,roughly one million kg, cal value,what quantity of materials would be required to were produced worldwide in 1990 (National Narcotics meet market need?Assuming that the agent would be uti- Intelligence Consumers Committee,1990),greatly in excess lized to treat an acute condition,that there existed a rela- of the examples required to meet an ethical pharmaceutical tively small patient population of only about 10,000 market.Clearly,capability is present if there is a stable and patients per year and that approximately 2 g of the agent bona fide market for the chemical substance.Finally,it would be required for a course of therapy,20 kg per year should be noted that the"worst case"might not be repre- of bulk active drug would be required to meet the market sentative.Natural product substances are often found in need.,Assuming again the“worst-case” scenario. their plant source at 0.1%to even 1.0%,orders of magni- 2x 10 kg of dry biomass per year would be required.That tude greater than the "worst-case."Further selection can may seem like a truly daunting or impossible quantity of often raise concentration of the desired natural product material to collect and process. in biomass to an even greater extent(Bruneton,1999)

and characterization of the natural product that occurs in plant biomass at this low concentration. Identification of biological activity, isolation of active product and determi￾nation of chemical structure require at most 50 mg of the chemical substance (Cremin and Zeng, 2002; Eldridge et al., 2002). Isolation of this amount of chemical substance requires about 5 kg of dry plant material. At this point, with the chemical substance isolated and characterized and its biological properties determined, a decision point is reached: Is the chemical structure novel? Does this sub￾stance represent a potential new prototype? If the answers to these questions are ‘‘yes’’, we now have a natural prod￾uct hit, and must decide whether to carry it forward into development. Proceeding to the next step means assessing the real potential of the substance. Confirmatory bioassays must be carried out to make sure that the suspected biological activity is actually present. These must be followed with secondary biological assays to gain a full understanding of the breadth and selectivity of the biological activity and preliminary toxicology tests (if it cures a particular disease but kills the patient, then it is not really likely to be a drug substance). Once all of that information is available, some initial in vivo evaluation must be carried out to determine that the agent has real promise both in terms of its efficacy and its toxicity in a ‘‘real world’’ situation. To carry out these assessments, approximately 400–500 mg of pure active chemical substance is needed. That represents a 10-fold increase in the plant material required; as much as 100 kg of biomass (dry weight) is needed for processing to gain this additional information. This requirement is not particularly daunting, and it is very probable that development would proceed to this stage. Success at this stage would suggest, then, that the agent would be carried forward into preclinical evaluation. This is where the quantity of dry biomass begins to look like a very daunting proposition. The quantity of pure chemical substance required for full preclinical development and a subsequent clinical trial is roughly 2 kg of pure product. Therefore, in the ‘‘worst-case’’ scenario for active product, (isolation yield from biomass of only 0.001%) 200,000 kg of dry plant biomass would be required to produce the required pure active product to this point. Next, should the substance be carried forward through development and demonstrated to have true pharmaceuti￾cal value, what quantity of materials would be required to meet market need? Assuming that the agent would be uti￾lized to treat an acute condition, that there existed a rela￾tively small patient population of only about 10,000 patients per year and that approximately 2 g of the agent would be required for a course of therapy, 20 kg per year of bulk active drug would be required to meet the market need. Assuming again the ‘‘worst-case’’ scenario, 2 · 106 kg of dry biomass per year would be required. That may seem like a truly daunting or impossible quantity of material to collect and process. However, considering this amount in the context of crop-based commodities, something that is more easily understood, this represents roughly 2200 tons of biomass, which is the equivalent of about 75,000 bushels of wheat, corn, soybeans or any other commodity. An average Amer￾ican farmer produces roughly this 75,000-bushel quantity or more each year. In this context, we are not talking about chopping down and processing entire tropical rainforests to obtain the 2 · 106 kg or more per year of dry plant biomass. Let us consider another scenario, where the agent is used to treat a chronic condition, the patient population is con￾siderably larger – 100,000 patients per year, and the agent has reasonable potency so that only ca. 50 mg per patient per day is required to treat the condition. Under these con￾ditions, 2000 kg of bulk active drug would be required to meet the market need. Again assuming the ‘‘worst-case’’ scenario of 0.001% of active product isolated from bio￾mass, 2 · 108 kg of biomass (dry weight) would be required to produce this 2000 kg per year of bulk active substance. The number, 2 · 108 kg, appears to be very large, but when placed again in the context of crop-based commodities such as wheat or corn or soybeans, it is obvious that this represents a modest production level. Indeed, many agri￾cultural counties of the United States produce as much or more than the 7.5 · 106 bushels of a commodity that the 2 · 108 kg represent. In this context it is clear that this quantity of biomass is readily obtainable. Two deliberately selected examples emphasize this point. Information on the worldwide production of marijuana and cocaine leads to the following observations: In 1996, an estimated 11,000 metric tons were produced worldwide with much of that produced in the United States (Gold￾berg, 2005). At a price of less than $2000 per pound, and considering all of the criminal penalties that would ensue if one were convicted of producing marijuana, it is clear that, when there is a market for a plant biomass, there will be an entrepreneurial effort to meet that market. Indeed, considering the billions of dollars spent each year to sup￾press drug plant production, it is easily appreciated that giving growers an alternate profitable and ethical crop to raise, will lead readily to the production of the necessary quantities of biomass for drug production to meet pharma￾ceutical application. In the case of cocaine, which is utilized as a nearly pure chemical entity (about $18,000 per kg at source) indeed a thousand tons, roughly one million kg, were produced worldwide in 1990 (National Narcotics Intelligence Consumers Committee, 1990), greatly in excess of the examples required to meet an ethical pharmaceutical market. Clearly, capability is present if there is a stable and bona fide market for the chemical substance. Finally, it should be noted that the ‘‘worst case’’ might not be repre￾sentative. Natural product substances are often found in their plant source at 0.1% to even 1.0%, orders of magni￾tude greater than the ‘‘worst-case.’’ Further selection can often raise concentration of the desired natural product in biomass to an even greater extent (Bruneton, 1999). J.D. McChesney et al. / Phytochemistry 68 (2007) 2015–2022 2019

2020 J.D.MeChesney et al Phytochemistry 68(2007)2015-2022 8.Meeting the supply challenge will usually involve developing an appropriate drying process. If natural products are to be produced for utilization in Once processing of the biomass is initiated,the extrac- the pharmaceutical industry,there will be certain criteria tion-purification system must be economical:it must be that a system of production must meet.First,it clearly efficient in its recovery of the natural product from the bio- must be economical.After all,if the drug costs hundreds mass.It must be safe in its operation,and the generation of to thousands of dollars per dose,there is no viable product. waste products must be minimized so that there is no del- However,it should be noted that recently approved thera- eterious environmental impact from the processing of the pies for life-threatening conditions,cancer,stroke,etc.,are biomass material.When systematic evaluation of a produc- often of such magnitude.Also,the production system must tion strategy for natural products is carried out.there is be sustainable and reliable.Patients will need the drug this evidence that the quantity of natural product substance year,next year and perhaps a decade from now,and a does not become a limitation either in development or ulti- source of that agent must be available to meet those med- mate commercialization of pharmaceuticals derived from ical needs.And finally,today's society requires that pro- natural products duction of natural products be environmentally safe. This point may be illustrated with the example of non-environmentally impacting.One cannot propose to Taxol -an anticancer agent of plant origin (Suffness, cut down the rainforests or denude the earth of a particular 1995).Taxol was initially discovered through the NCI species for the production of a natural product. program for evaluation of plant preparations for antican- To meet these criteria and establish a viable produc- cer activity (Kingston et al.,1993;Suffness,1995).In tion system,all the steps of production of a natural 1962,USDA botanist Arthur Barkley collected Taxus product must be systematically evaluated.First,a supe- brevifolia and submitted that biomass to the NCI's anti- rior source of that substance must be identified.A strain cancer evaluation effort.In 1964.an extract of the bark or variety of the species must be discovered that has a was shown to be highly cytotoxic in vitro to cancer cells. high and consistent concentration of the natural product This material was re-collected and the biological activity or a precursor of the natural product that can be con- was confirmed in certain animal models of cancer.By verted economically by semi-synthesis to the final bulk 1967,3000 pounds of bark were collected and processed, active product. leading,in 1971,to the structure elucidation of Taxol Once that superior source has been identified,an unin- (Wani et al.,1971).Efforts by Susan Horowitz (Suffness, terruptible and stable supply of that material must be 1995)in the late 1970s showed that Taxol had a unique secured (Khan,2006).Ordinarily this means that an agro- mechanism of action in its suppression of the growth of nomic system for biomass production must be developed, cancer cells.In 1977.this led to its extensive evaluation i.e.one must bring the source into cultivation.This allows in animal models of cancer where it showed high activity the full expression of the genetic capability of the cultivar. and led to its designation for development.In 1983 Climate and soil types must be matched to the require- Taxol entered human clinical trials.By 1988,initial ments of the plant;the impact of fertilization,irrigation, clinical results in ovarian cancer were very encouraging etc..on the production of the biomass and its chemical con- and a major effort was initiated.This was followed by stituents must be understood;and,generally,the econom- the development of a system for the economic produc- ical growth and cultivation of the material must be tion of Taxol and final development for approval for explored.In the future,a plant's production of secondary utilization in the treatment of cancer.In 1992,Taxol substances may be controlled with growth regulators of was approved for the treatment of refractory ovarian one sort or another.Finally,Good Agriculture Practices cancer.In 1993,Bristol-Myers Squibb Company had (i.e.,"GAP")(World Health Organization,2003)should sales of more than $150 million of Taxol.BMS sales be utilized in this agronomic production. of Taxol grew to nearly $2 billion,by 2000,when The successful development of biomass production will Taxol became generic (www.cancerpage.com/news/arti- dictate development of appropriate harvest techniques. cle.asp?id =4866).Thus,it can be seen that this very Topics to consider are determination of maximum concen- complex natural product of plant origin has great utility tration of active drug product in the plant during the grow- in the treatment of human cancer and that because of its ing season and the handling of freshly harvested biomass to complex chemical structure,it will not likely be econom- retain drug content.And finally,in order to maintain an ically prepared by synthesis.Consequently,we must rely economic system of production,mechanization of the har- on isolation from a natural source of the agent or a nat- vest process must be addressed. ural product semi-synthetic precursor.Indeed,Bristol- Harvested biomass will require an economic processing Myers Squibb evolved a system of production based facility that is capable of processing biomass for isolation upon isolation of a precursor of Taxol from the leaves of the active product over an entire calendar year,not just or needles of cultivated Taxus baccata or T.wallichiana immediately after harvesting.Therefore,technology must that will provide the hundreds of kilograms of Taxol be developed to stabilize the biomass so that it retains drug required per year for the future treatment of cancer content during storage before its ultimate processing.This patients (Jacoby,2005)

8. Meeting the supply challenge If natural products are to be produced for utilization in the pharmaceutical industry, there will be certain criteria that a system of production must meet. First, it clearly must be economical. After all, if the drug costs hundreds to thousands of dollars per dose, there is no viable product. However, it should be noted that recently approved thera￾pies for life-threatening conditions, cancer, stroke, etc., are often of such magnitude. Also, the production system must be sustainable and reliable. Patients will need the drug this year, next year and perhaps a decade from now, and a source of that agent must be available to meet those med￾ical needs. And finally, today’s society requires that pro￾duction of natural products be environmentally safe, non-environmentally impacting. One cannot propose to cut down the rainforests or denude the earth of a particular species for the production of a natural product. To meet these criteria and establish a viable produc￾tion system, all the steps of production of a natural product must be systematically evaluated. First, a supe￾rior source of that substance must be identified. A strain or variety of the species must be discovered that has a high and consistent concentration of the natural product or a precursor of the natural product that can be con￾verted economically by semi-synthesis to the final bulk active product. Once that superior source has been identified, an unin￾terruptible and stable supply of that material must be secured (Khan, 2006). Ordinarily this means that an agro￾nomic system for biomass production must be developed, i.e. one must bring the source into cultivation. This allows the full expression of the genetic capability of the cultivar. Climate and soil types must be matched to the require￾ments of the plant; the impact of fertilization, irrigation, etc., on the production of the biomass and its chemical con￾stituents must be understood; and, generally, the econom￾ical growth and cultivation of the material must be explored. In the future, a plant’s production of secondary substances may be controlled with growth regulators of one sort or another. Finally, Good Agriculture Practices (i.e., ‘‘GAP’’) (World Health Organization, 2003) should be utilized in this agronomic production. The successful development of biomass production will dictate development of appropriate harvest techniques. Topics to consider are determination of maximum concen￾tration of active drug product in the plant during the grow￾ing season and the handling of freshly harvested biomass to retain drug content. And finally, in order to maintain an economic system of production, mechanization of the har￾vest process must be addressed. Harvested biomass will require an economic processing facility that is capable of processing biomass for isolation of the active product over an entire calendar year, not just immediately after harvesting. Therefore, technology must be developed to stabilize the biomass so that it retains drug content during storage before its ultimate processing. This will usually involve developing an appropriate drying process. Once processing of the biomass is initiated, the extrac￾tion–purification system must be economical; it must be efficient in its recovery of the natural product from the bio￾mass. It must be safe in its operation, and the generation of waste products must be minimized so that there is no del￾eterious environmental impact from the processing of the biomass material. When systematic evaluation of a produc￾tion strategy for natural products is carried out, there is evidence that the quantity of natural product substance does not become a limitation either in development or ulti￾mate commercialization of pharmaceuticals derived from natural products. This point may be illustrated with the example of Taxol – an anticancer agent of plant origin (Suffness, 1995). Taxol was initially discovered through the NCI program for evaluation of plant preparations for antican￾cer activity (Kingston et al., 1993; Suffness, 1995). In 1962, USDA botanist Arthur Barkley collected Taxus brevifolia and submitted that biomass to the NCI’s anti￾cancer evaluation effort. In 1964, an extract of the bark was shown to be highly cytotoxic in vitro to cancer cells. This material was re-collected and the biological activity was confirmed in certain animal models of cancer. By 1967, 3000 pounds of bark were collected and processed, leading, in 1971, to the structure elucidation of Taxol (Wani et al., 1971). Efforts by Susan Horowitz (Suffness, 1995) in the late 1970s showed that Taxol had a unique mechanism of action in its suppression of the growth of cancer cells. In 1977, this led to its extensive evaluation in animal models of cancer where it showed high activity and led to its designation for development. In 1983, Taxol entered human clinical trials. By 1988, initial clinical results in ovarian cancer were very encouraging and a major effort was initiated. This was followed by the development of a system for the economic produc￾tion of Taxol and final development for approval for utilization in the treatment of cancer. In 1992, Taxol was approved for the treatment of refractory ovarian cancer. In 1993, Bristol-Myers Squibb Company had sales of more than $150 million of Taxol. BMS sales of Taxol grew to nearly $2 billion, by 2000, when Taxol became generic (www.cancerpage.com/news/arti￾cle.asp?id = 4866). Thus, it can be seen that this very complex natural product of plant origin has great utility in the treatment of human cancer and that because of its complex chemical structure, it will not likely be econom￾ically prepared by synthesis. Consequently, we must rely on isolation from a natural source of the agent or a nat￾ural product semi-synthetic precursor. Indeed, Bristol￾Myers Squibb evolved a system of production based upon isolation of a precursor of Taxol from the leaves or needles of cultivated Taxus baccata or T. wallichiana that will provide the hundreds of kilograms of Taxol required per year for the future treatment of cancer patients (Jacoby, 2005). 2020 J.D. McChesney et al. / Phytochemistry 68 (2007) 2015–2022

J.D.McChesney et al.Phytochemistry 68(2007)2015-2022 2021 9.Conclusion Fullbeck,M.,Michalsky,E.,Dunkel,M.,Preissner,R.,2006.Natural products:sources and databases.Nat.Prod.Rep.23,347-356. Plant derived natural products hold great promise for Goldberg,R..2005.Drugs Across the Spectrum.Thomson Brooks Cole, Boston,MA (Chapter 12). discovery and development of new pharmaceuticals.Care- Gomord,V.,Chamberlain,P.,Jefferis,R.,Faye,L..2005.Biopharma- ful consideration of the entire process of discovery and ceutical production in plants:problems,solutions and opportunities. development-a "systems"approach-will be required Trends Biotechnol.23(11),559-565. to realize this great promise effectively.While it is recog- Gross,J.H.,2006.Mass Spectrometry A Textbook.Springer. nized that each solution to the supply issue may seem to Jacoby,M.,2005.The top pharmaceuticals that changed the world.Taxol. Chem.Eng.News 83(25),3. be a specific case,we believe all solutions really represent Jung,H.G.,2006.Chemical genomics with natural products.J.Microbiol. variations on the theme and can be effectively identified Biotech.16(5).65l-660. and implemented by a systematic endeavor.The percep- Khan,I.A.,2006.Issues to botanicals.Life Sci.78.2033-2038. tions limiting interest in the utilization of plant derived nat- Kingston,D.G.I.,Molinero,A.A.,Rimoldi,J.M.,1993.In:Progress in ural products can be readily addressed to return them to the Chemistry of Organic Natural Products,vol.61.Springer Verlag. New York. their preeminence in pharmaceutical discovery and Kipling.R..1910."Our Fathers of Old"in Rewards and Fairies. development. Doubleday,Page and Company,New York. Koehn,F.E..2005.The evolving role of natural products in drug discovery.Nature 4,206-220. Acknowledgements Korfmacher,W.A.,2005.Principles and applications of LC-MS in new drug discovery.Drug Discov.Today 10(20),1357-1367. Lawrence,G.H.M.,1951.The Taxonomy of Vascular Plants.The The authors thank Janet Poley for her assistance in the Macmillan Company,New York. literature searches and preparation of this manuscript. Lipinski,C.A.,Lombardo,F..Dominy,B.W.,Feeney.P.J..1997. Experiments and computational approaches to estimate solubility and permeability in drug discovery and development settings.Adv. Drug.Del.Rev.23,3-25. References Littleton,J.,Rogers,T.,Falcone,D.,2005.Novel approaches to plant drug discovery based on high throughput pharmacological screening Balunas,M.J..Kinghorn,A.D.2005.Drug discovery from medicinal and genetic manipulation.Life Sci.78.467-475. plants.Life Sciences 78,431-441. National Narcotics Intelligence Consumers Committee,1990.The Supply Basara,L.R.,Montagne,M.,1994.The Food and Drug Administration of Illicit Drugs to the United States.Drug Enforcement Administra- and Drug Approval.Pharmaceutical Products Press,New York,pp tion,Office of Intelligence,Washington,DC. 77-108. 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Chemistry.Pergamon,New York. Niessen.W.M.A.,1999.Liquid Chromatography-Mass Spectrometry. Cragg,G.M.,Kingston,D.G.I.,Newman,D.J.,2005.Anticancer Agents Marcel Dekker,Inc.,New York. from Natural Products.CRC Press,Taylor Francis Group,Boca Ortholand,J-Y.,Ganesan,A.,2004.Natural products and combinatorial Raton,FL. chemistry:back to the future.Curr.Opin.Chem.Biol.8(3),271-280. Cremin,P.A.,Zeng,L.,2002.High-throughput analysis of natural Paterson,I.,Anderson,E.A.,2005.The renaissance of natural products as product compound libraries by parallel LC-MS evaporative light drug candidates.Science 310,451-453. scattering detection.Anal.Chem.74,5492-5500 Pauli,G.,2006.Countercurrent chromatography of natural products. Croasmun,W.R.,Carlson,R.M.K.,1994.Two-dimensional NMR CCC 2006.In:The 4th International Conference on Countercurrent Spectroscopy:Applications for Chemists and Biochemists,second ed. Chromatography,August 8-11.2006.Bethesda,MD. Wiley-VCH. 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9. Conclusion Plant derived natural products hold great promise for discovery and development of new pharmaceuticals. Care￾ful consideration of the entire process of discovery and development – a ‘‘systems’’ approach – will be required to realize this great promise effectively. While it is recog￾nized that each solution to the supply issue may seem to be a specific case, we believe all solutions really represent variations on the theme and can be effectively identified and implemented by a systematic endeavor. The percep￾tions limiting interest in the utilization of plant derived nat￾ural products can be readily addressed to return them to their preeminence in pharmaceutical discovery and development. Acknowledgements The authors thank Janet Poley for her assistance in the literature searches and preparation of this manuscript. References Balunas, M.J., Kinghorn, A.D., 2005. Drug discovery from medicinal plants. Life Sciences 78, 431–441. Basara, L.R., Montagne, M., 1994. 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2022 J.D.McChesney et al.Phytochemistry 68 (2007)2015-2022 Vuorela,P..2004.Natural products in the process of finding new drug bioanalytical chemistry of natural products and drugs,chemotherapy of candidates.Curr.Med.Chem.11 (11).1375-1389. tropical diseases,and the control of plant growth and development.Most Wani,M.C.,Taylor,H.L..Wall,M.E.,Coggon,P.,McPhail,A.T.,1971. recently he has focused on development of biologically active natural Plant antitumor agents.VI.The isolation and structure of taxol,a products as pharmaceuticals,especially as cancer chemotherapeutics.Dr. novel antileukemic and antitumor agent from Taxus brevifolia.J.Am. McChesney has received significant funding from the NIH.NSF.WHO. Chem.Soc.93(9),2325-2327. FDA and USDA.As a recognized expert in medicinal plant development, Waterman,P.G.,1992.Secondary metabolites:their function and evolu- he frequently lectures and has authored more than 180 peer-reviewed tion.In:Ciba Foundation Symposium,vol.171.Wiley,Chichester publications and nearly three-dozen patents. England,pp.255-275. Wilson,R.M.,Danishefsky,S.,2006.Small molecule natural products in Sylesh Kumar Venkataraman,received his the discovery of therapeutic agents:the synthesis connection.J.Org. Bachelor's degree in Chemistry (1991) Chem.71(22),8329-8351. from St.Joseph's College and a Master's World Health Organization,2002.Traditional and Alternative Medicine, degree in Chemistry (1993)from Bha- Fact Sheet 271.World Health Organization,Geneva. rathidasan University,both in Tiruchi- World Health Organization.2003.WHO Guidelines on Good Agricul- rappalli,India.He received his Ph.D. tural and Collections Practices (GACP)for Medicinal Plants.World (1999)in Chemistry (synthesis of biologi- Health Organization,Geneva. cally active molecules)from the Indian Institute of Chemical Technology James D.McChesney,Chief Scientific Hyderabad,India and a Post Graduate Officer of Natural Products for Tapestry Diploma in Marketing Management Pharmaceuticals,Inc.(formerly NaPro (1998)from the Indira Gandhi National BioTherapeutics,Inc.)and ChromaDex, Open University,New Delhi,India.Dr. Inc.,both located in Boulder,Colorado Venkataraman pursued post-doctoral received a B.Sc.in Chemical Technology research at the University of Texas Southwestern Medical Center at from lowa State University,M.A.in Dallas,Texas,Wayne State University,Detroit,MI and at the University Botany,and Doctorate in Organic of Connecticut,Storrs,CT.He has been with Tapestry Pharmaceuticals. Chemistry from Indiana University in Inc.since 2004. Bloomington,Indiana focusing on natural products.Dr.McChesney has a long dis- John Theodore Henri Jr.was born and grew tinguished teaching career as a Professor up in Hyderabad,India.He received his of Botany and Medicinal Chemistry at the Bachelors and Masters degrees from University of Kansas and as Professor of Osmania University and his Ph.D.under Pharmacognosy at the University of Mississippi.He also served as an Prof.A.V.Rama Rao at the Indian Institute advisor to the World Health Organization on Traditional Medicines and of Chemical Technology on the total syn- anti-malarial drug development,and to UNESCO in Natural Products thesis of pironetin.He then pursued post- Chemistry.In 1985,he taught Natural Products Chemistry in Brazil as a doctoralstudiesunder Prof.GundaI.Georg Fulbright Fellow.From 1978 to 1986,he chaired the Department of working on the total synthesis ofepothilones Pharmacognosy at the University of Mississippi.He was Director of the and syntheses of prodrugs.In the pharma- Research Institute of Pharmaceutical Sciences,and later also Director of ceutical industry since 2001,John works on the National Center for the Development of Natural Products.In 1996 he the discovery of new natural product joined Tapestry.His research interests include the chemistry,metabolism, derived drugs and targeting of cytotoxics function and production of biologically active organic natural products, using peptides,proteins and lipids

Vuorela, P., 2004. Natural products in the process of finding new drug candidates. Curr. Med. Chem. 11 (11), 1375–1389. Wani, M.C., Taylor, H.L., Wall, M.E., Coggon, P., McPhail, A.T., 1971. Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J. Am. Chem. Soc. 93 (9), 2325–2327. Waterman, P.G., 1992. Secondary metabolites: their function and evolu￾tion. In: Ciba Foundation Symposium, vol. 171. Wiley, Chichester England, pp. 255–275. Wilson, R.M., Danishefsky, S., 2006. Small molecule natural products in the discovery of therapeutic agents: the synthesis connection. J. Org. Chem. 71 (22), 8329–8351. World Health Organization, 2002. Traditional and Alternative Medicine, Fact Sheet # 271. World Health Organization, Geneva. World Health Organization, 2003. WHO Guidelines on Good Agricul￾tural and Collections Practices (GACP) for Medicinal Plants. World Health Organization, Geneva. James D. McChesney, Chief Scientific Officer of Natural Products for Tapestry Pharmaceuticals, Inc. (formerly NaPro BioTherapeutics, Inc.) and ChromaDex, Inc., both located in Boulder, Colorado received a B.Sc. in Chemical Technology from Iowa State University, M.A. in Botany, and Doctorate in Organic Chemistry from Indiana University in Bloomington, Indiana focusing on natural products. Dr. McChesney has a long dis￾tinguished teaching career as a Professor of Botany and Medicinal Chemistry at the University of Kansas and as Professor of Pharmacognosy at the University of Mississippi. He also served as an advisor to the World Health Organization on Traditional Medicines and anti-malarial drug development, and to UNESCO in Natural Products Chemistry. In 1985, he taught Natural Products Chemistry in Brazil as a Fulbright Fellow. From 1978 to 1986, he chaired the Department of Pharmacognosy at the University of Mississippi. He was Director of the Research Institute of Pharmaceutical Sciences, and later also Director of the National Center for the Development of Natural Products. In 1996 he joined Tapestry. His research interests include the chemistry, metabolism, function and production of biologically active organic natural products, bioanalytical chemistry of natural products and drugs, chemotherapy of tropical diseases, and the control of plant growth and development. Most recently he has focused on development of biologically active natural products as pharmaceuticals, especially as cancer chemotherapeutics. Dr. McChesney has received significant funding from the NIH, NSF, WHO, FDA and USDA. As a recognized expert in medicinal plant development, he frequently lectures and has authored more than 180 peer-reviewed publications and nearly three-dozen patents. Sylesh Kumar Venkataraman, received his Bachelor’s degree in Chemistry (1991) from St. Joseph’s College and a Master’s degree in Chemistry (1993) from Bha￾rathidasan University, both in Tiruchi￾rappalli, India. He received his Ph.D. (1999) in Chemistry (synthesis of biologi￾cally active molecules) from the Indian Institute of Chemical Technology, Hyderabad, India and a Post Graduate Diploma in Marketing Management (1998) from the Indira Gandhi National Open University, New Delhi, India. Dr. Venkataraman pursued post-doctoral research at the University of Texas Southwestern Medical Center at Dallas, Texas, Wayne State University, Detroit, MI and at the University of Connecticut, Storrs, CT. He has been with Tapestry Pharmaceuticals, Inc. since 2004. John Theodore Henri Jr. was born and grew up in Hyderabad, India. He received his Bachelors and Masters degrees from Osmania University and his Ph.D. under Prof. A.V. Rama Rao at the Indian Institute of Chemical Technology on the total syn￾thesis of pironetin. He then pursued post￾doctoral studies under Prof. Gunda I. Georg working on the total synthesis of epothilones and syntheses of prodrugs. In the pharma￾ceutical industry since 2001, John works on the discovery of new natural product derived drugs and targeting of cytotoxics using peptides, proteins and lipids. 2022 J.D. McChesney et al. / Phytochemistry 68 (2007) 2015–2022