《天然药物化学》课程参考文献（天然药物研究与开发）Natural products in drug discovery

Phytochemistry Reviews 1: 261–273, 2002. © 2003 Kluwer Academic Publishers. Printed in the Netherlands. 261 Natural products in drug discovery – Creating a new vision Geoffrey A. Cordell College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St., Chicago, IL 60612, U.S.A. (Tel: 312-413- 5381; Fax: 312-996-7107; E-mail: cordell@uic.edu) Key words: biotechnology, creative vision, dietary supplements, natural products, sustainable drug discovery Abstract “If only they had chosen to develop natural product drugs in a sustainable manner at the turn of the century”. In 2050, when the Earth has a population of at least 9 billion, will this be our legacy as the world contemplates the costs and availability of synthetic and gene-based products for primary health care? For most people in the world, plants, in their various forms, remain a primary source of health care. However, in the developed countries, natural products derived from plants assume a very minor role as prescription and over-the-counter products, even with the widespread use of phytotherapeutical preparations. With the continuing decline of natural products in large scale, ultrahigh-throughput screening programs in pharmaceutical industry, and acknowledging the recent history of the relationship between humankind and the Earth, it is essential that we consider what are the health care issues that we are leaving for our descendants? Where do our responsibilities as global citizens and scientists coalesce? What is the vision for natural product research that we must create now in order to maintain the choices of drug discovery and pharmaceutical development for future generations? In order to assist us in creating this vision, we will examine some facets of how natural products must be involved globally in a sustainable manner for improving health care. We will discuss access to the biome, the acquisition, analysis and dissemination of plant knowledge, the safety and efficacy of traditional plant remedies, analytical and biotechnology development, and natural product structure diversification and drug discovery potential. Finally, we will address the question of who will fund this vision? Abbreviations: ASP – American Society of Pharmacognosy; CBD – Convention on Biological Diversity; CYTED – Ciencia y Technologia para el Desarrollo; DAAD – Deutscher Akademischer Austausch Dienst; EU – European Union; GA – Gesellschaft für Arzneipflanzenforschung; IFS – International Foundation for Science; IUPAC – International Union for Pure and Applied Chemistry; JSPS – Japan Society for the Promotion of Science; NATO – North Atlantic Treaty Organization; NIE – National Institute for the Environment; NIH – National Institutes of Health; NSF – National Science Foundation; PSE – Phytochemical Society of Europe; RSC – Royal Society of Chemistry; SRC – Science Research Council; TWAS – Third World Academy of Science; UNIDO – United Nations International Development Organization; UNDP – United Nations Development Program; WHO – World Health Organization; WRI – World Resources Institute; WWF – World Wildlife Fund. The current situation Human inquisitiveness has extended to many corners of the Earth, to our solar system, and to the distant great clouds of nebulae which appear to be forming and reforming billions of suns and their solar systems. Inherent in the very existence of humankind has been the incessant desire to expand the boundaries of our knowledge and creativity, and thus a new vision of how life might continuously be improved on a global basis. For many humans, access to travel, to television, and to electronic communication has allowed, indeed encouraged us, to engage with the breadth and depth of human and biological experiences across national boundaries and up and down the global ecochasms

262 The treasures now available from delving into these rich stores of biological and mineral wealth are amazing. Everything of a material nature that constitutes what we respectively regard as civilization has originated through our creative adaptation of the products from the continuous, transformational recycling of Earth’s resources that has endured for over 4.5 billion years. As the application of our ingenuity to ameliorate disease and to prolong life substantially has increased, particularly in the last century, so have the issues which we must boldly face. This article is about one such issue and the creativity needed to address it. In 1850, the world’s population was 1 billion (The World Almanac and Book of Facts, 2001), and by 1930 had doubled (80 years). Within 45 years, it had doubled again to 4 billion, and by October 1999 had reached 6 billion. According to the Bureau of the Census, U.S. Dept of Commerce, global population will exceed 9 billion by 2050. Is it rational to think that the Earth has the physical and intellectual resources to sustain such a population for even one generation? In truth, we know little of the assets or the capacity of the Earth to sustain such an exploding population, but what we do know is not very encouraging. Approximately 1 billion barrels of oil are known in reserves, or approximately 70 years supply at present usage rates. Non-reusable fossil fuels approximate 82% of the present energy usage in the U.S. (The World Almanac and Book of Facts, 2001). Three major industries, textiles, energy, and plastics have initiated substantial research programs aimed at examining the potential to develop their respective core resources in a sustainable manner (Reisch, 2001). Stunningly, drug discovery at all of the major pharmaceutical companies remains focused on the utilization of non-renewable resources for most of their drug discovery, development, and production. Although some efforts are currently aimed at the “greening” of numerous chemical industrial processes (Rouhi, 2002), there is no long term effort underway to examine how drugs will be made available globally in a sustainable manner from natural sources for future generations. In a series of articles over the past fifteen years, I have tried to illustrate some of the issues which I am convinced the field is facing, and how they might be addressed (Cordell, 1987a, 1987b, 1990a, 1990b, 1991, 1992, 1993, 1994, 1995a, 1995b, 1999, 2000a, 2000b, 2001a, 2001b, 2002a, 2002b). I have tried to portray some of the successes, some of the missing elements in existing programs, and some of the potential opportunities. In this article, because we are rapidly running out of time and resources to make the needed changes, I am adopting a different approach, and will make some quite specific proposals for how to begin a dialogue for the global benefit of human health based on natural products. As natural product scientists, we must recognize that we have important societal responsibilities, some of which will be presented towards the end of this presentation. One approach to this awareness is to ask ourselves the personal question “Whom are our studies in the natural sciences serving?” To begin to formulate a response, a considered discussion of the purposes, the aims, and the future of the natural product sciences is needed. Recognizing that pharmacognosy is “the study of biologically active natural products” (Cordell, 1990a), in the broader sense we can ask, “What is pharmacognosy for?” Typically, international science conferences focus on past achievements, on results already generated, and, in many instances, already published. The presumption of a competitive environment frequently inhibits the generation of new ideas to be pursued, of new experiments to be proposed, for the fear of them being “stolen”. While from a life-long learning perspective such a presentation may be useful, from a future thinking perspective these meetings don’t challenge the integrity or the societal impact of the efforts that are being made. In addition, they do not utilize the collective talents available to create new initiatives, or even think in an open manner about the role of our sciences in a future world. As we shall see, there is a desperate need to create such opportunities for examining the options ahead. And how can the development of such plans become a collective vision? An international forum (or series of meetings) is needed to develop innovative programs for the future of the natural product sciences for the benefit of humankind. The statistics regarding the use of natural products as drugs are now well-known and have been presented and discussed elsewhere (Farnsworth and Morris, 1976; Cragg et al., 1997; Newman et al., 2000; Rates, 2001). Global sales of phytochemical products will be valued at about $31 billion in 2002 (Anon, 1998), and about 50% of the prescription products in various countries in Europe and the US are either natural products or are natural product derivatives (O’Neill and Lewis, 1993). However, many people in the pharmaceutical industry, in the medical, dental, and nursing professions, and in the public at large, are unaware of this critical role that nature plays in providing

263 vital drugs for health care on a daily basis. In part, this has probably occurred as we have lost the connections between ourselves and nature and between food and disease treatment and prevention. This background of achievement in discovering and developing drugs from natural sources (higher and lower plants, marine organisms and bacteria) for human health over the past 200 years does not impress the management of the major pharmaceutical companies in the world to continue to engage in natural product drug discovery; quite the reverse. Several major companies in the past few years (Abbott, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Merck, and Novartis) have essentially abandoned their natural product drug discovery programs. It should be noted that this list includes several companies for whom natural product drug sales exceed $1 billion per year. For example, sales of paclitaxel (taxol) for BristolMyersSquibb in 2000 were over $1.5 billion. At the global level of the major international agencies there are apparently no major natural product drug discovery programs underway, and quite limited programs at WHO aimed at enhancing the safety of traditional medicines (vide infra). For a number of reasons, including the dire need for new drugs for a host of tropical diseases, for many diseases which are developing drug resistance, and for the purpose of serving as templates for drug design and development candidates, this situation is both appalling and alarming. It will not suffice to serve for the future, and is not a situation that we can choose to ignore in the present. Let us begin then with a brief appreciation of the natural products derived from plants which are consumed every day of our lives on a global basis. There is paper, there are the foodstuffs, the flavors and the spices, the perfumes and cosmetics, and the health grooming products, and there are the prescription and over-the counter products. In addition, there are numerous extracts and plant materials that are used on a daily basis all over the world for a variety of purposes, including as medicinal agents. It was estimated many years ago that over 80% of the worlds’ population uses plant materials as their source of primary health care (Farnsworth et al., 1985). Presumably, this number is even higher today as populations in the developing world have continued to expand steadily. During the past ten years there has been a dramatic increase in the use of phytotherapeutical products in many developed countries. In the United States, for example, approximately $4.2 billion of such dietary supplements were sold in 1998, although sales have declined since then (Anon, 2001b). In many countries in Europe, there are regulations which govern the labeling and use of phytotherapeutical entities. However, elsewhere in the world, there arises a very interesting and dramatic connection between the medicinal uses of plant materials in the developed and the developing worlds: NEITHER GROUP OF PRODUCTS IS REGULATED. Two aspects of this situation are particularly troubling. The first is that it is very much the era of “Buyer Beware” in both instances. Whether you are going to your local health food store or your local shaman or curandero, the fact is that you are “buying blind”. Continuation of this situation, on a global basis, substantially undermines the credibility of natural product research and the role that it should be playing in health care. We need to re-vision this role for the stature of our science. This dangerous and unacceptable situation has arisen in developed countries because of the common belief in two myths. The first myth is that natural products are safe, particularly if they have been used for hundreds of years in a system of traditional medicine. The second myth is that the contents of a box or a bottle of a dietary supplement which contains plant or fungal or marine products are somehow regulated. This arises, in part, because of the placement of rows of dietary supplements across the store aisle from OTC products, which are regulated. Do we as natural product scientists wish to perpetuate this situation? Or do we have a different vision? What do consumers all over the world have the right to expect for a plant-derived product in their marketplace? Probably the first aspect is plant authentication. Namely, that the correct plant part, of the correct genus and species is contained in the package. Consumers also need to know that their product is not contaminated with insects, pesticides, herbicides, heavy metals, microbial and fecal matter, and radiation. Consumers should be assured that the product they are purchasing is not adulterated by materials (natural or synthetic) which are either not approved, or not approved for the stated use. In addition to botanical standardization, consumers have the right to expect a product that is consistent, on a batch-to-batch basis, chemically and biologically. When a consumer buys a dietary supplement they should know how long the product will remain active. That a bag of candy has more information on it, and has more regulation involved with its presentation than a phytotherapeutical product, is absurd. Finally, when one buys a phytotherapeutical product, as when one buys a cup of coffee, you expect that it will work. That the desired

264 effect will be achieved. For how many of the myriad of products on the market has efficacy been scientifically established? In addition, many consumers are taking phytotherapeuticals and prescription or OTC drugs at the same time. Yet the interactions between these categories of products are not well studied and documented (Kroll, 2001). Do we have a different vision? The uses of many (approximately 74%) of the plant-derived drugs that are presently marketed are similar or identical to their ethnomedical use (Farnsworth, 1988; Cordell et al., 2001). Yet, the knowledge of the medicinal use of plants has not been fully catalogued and accumulated, and there are now substantive issues involved in collecting that information following the Convention on Biological Diversity (CBD)(Anon, 2001c). Shamans are not training new apprentices (Balick and Cox, 1996; Cox, 2000), and thus the knowledge of the use of plants is being lost. We recognize that on a global basis, as a result of population growth and issues related to deforestation for timber and farmland, biodiversity, in all its forms, is decreasing (Wilson, 1988). In spite of the exorbitant amortized costs (currently estimated at $500 million) to bring a single new drug to market, and the pressures of a potentially changing patent situation, there is a continuing need for the discovery of new medicinal agents. Resistance to known chemotherapeutic agents, including anticancer, antiviral, antifungal, and antibacterial agents is steadily increasing (Rothenberg and Ling, 1989). New diseases are appearing requiring new drugs, and old diseases, once thought to have been eradicated, are reappearing. Yet, as mentioned above, even though the role of natural products as pharmaceutical agents is wellestablished, pharmaceutical companies are eliminating such discovery programs. Why? Before answering that question, with a somewhat controversial answer, it is important to understand a little about the early stages of how new medicinal agents are currently discovered. For those agents will be the new drugs in the marketplace for the next 15–20 years. The discovery of drugs is focused on evaluating a “library” of diverse chemical entities, usually in quite pure form and set-up in 384 or 1536-well plates, against a primary bioassay. Samples which provide a positive response to established criteria are then moved to the next stage of evaluation (frequently a secondary bioassay or a set of chemical inclusion criteria). The primary bioassay is often enzyme or receptor-based, and each of the steps, from construction of the library to the processing of the data from the tests, is fully automated. In this way, it is quite routine for a company to evaluate 1.5 to 2 million samples in a particular bioassay in a one to two month period (Thayer, 1998). Depending on their resources and their therapeutic interests, companies will run 15- 50 bioassays a year. The “library” and its construction (i.e. which samples are included for bioassay) therefore becomes a very critical aspect of the discovery process, and much consideration is given by companies as to the nature of the samples to be screened from a much larger corporate library of samples. Some aspects of the types of samples which might be included have been discussed previously. However, as new corporate mergers have taken place in the past few years (e.g. GlaxoWellcome and SmithKline and Pfizer and Pharmacia), a new phenomenon is occurring as these corporate libraries are being merged. The question now arises of what samples (i.e. how many of a 3 million sample collection?) are to be screened because of cost and time considerations. Where do natural products “fit” in these libraries? For those established natural products which are included in the libraries as individual compounds this is not a problem, because they are classed in the same way as a synthetic or semi-synthetic compound. It is worth noting at this point that for the class of compounds known as alkaloids 74% of the known compounds have never been evaluated against a single bioassay (Cordell et al., 2001). For an extract derived from a plant, a marine organism, a fungus or a bacteria, the situation is quite different. And it is at this point where the potential impact of natural products in the discovery process is being lost. It is important to state, very clearly, that the major pharmaceutical companies are no longer interested in the evaluation of natural product extracts. Consequently, they are eliminating all of those activities related to natural products from their basic discovery programs. The reasons are quite simple. Firstly, when an extract shows activity in a bioassay (i.e., is a “hit”), the active principle must be isolated and characterized. This is expensive and may take 1–4 months, depending on the availability of an appropriate amount of extract or plant material, the turnaround time for bioassay data, and the ease of unambiguously determining the structure (Corley and Durley, 1994). By this time, the other (synthetic) “hits” have been moved to the next stage of decision-making and the natural product is left behind. And that is assuming that recollection of the plant is not necessary, and that the extract of the recollected

265 plant retains the original biological activity. Two other factors also come into consideration before involving natural products in a drug discovery program; intellectual property issues and relative cost to obtain a “lead”. The distinction between a “hit” and a “lead” has been explained elsewhere (Cordell, 2000a), and focuses on the level of preliminary chemical and biological studies, and the availability of the compound to enter the next stages of development. Having an adequate and sustained supply of a biologically active natural product available for more extensive animal pharmacology is a frequent deterrent to the further development of that compound. For most scientists working in the area of natural product drug discovery, the intellectual property issues are now daunting. In the years since the Convention on Biological Diversity was signed by all of the major countries of the world (except the USA and Thailand), numerous countries in both the temperate and tropical areas of the world have put in place various forms of rules, regulations, legislation, and executive orders which control the acquisition of all biological materials and indigenous knowledge within their borders (Anon, 2001a). For research groups, both academic and industrial, in countries all over the world, these changes have fundamentally changed their modus operandi. It is no longer possible to collect a plant or a soil sample or a marine organism, even from your own country, without prior approval. Multilateral agreements between institutions and agencies in countries to access biological materials often take years to negotiate and finalize. Sometimes, even after substantial investment of time, money and personal effort, developing an agreement becomes impossible as governments, and their views, change. Pharmaceutical industry, which is operating in a very highly competitive environment to develop a new therapeutic entity based on rapidly changing science, has no patience for such a scenario. As a consequence, the hope that the CBD would lead to a higher level of international collaboration (including the involvement of the major drug companies) to investigate the biome for the potential to enhance human health has not materialized; indeed the effect has been the opposite. The corporate focus is set on combinatorial chemistry based on the identification of “hits” from individual synthetic or natural products present in their vast libraries (Adang and Hermkens, 2001), coupled with computational drug design (Clark and Pickett, 2000). There are significant social and ethical issues in this overall approach by pharmaceutical companies. The first matter of concern is that the drugs that are being developed as a result of this approach are not sustainable. Their creation and production continuously depletes the non-renewable resources (oil and coal) of the Earth. For example, only 11% of the 252 drugs on the list of those regarded as basic and essential for global human health by WHO are derived from plants (Rates, 2001). Secondly, the drugs that are being developed are not for a global population, but for a privileged few in the developed and developing world who either have the health insurance coverage (private or national), or the personal financing to pay for a prescription product (and the research behind it). A major rethinking of our global priorities for drug discovery for health is needed to redress this health care imbalance. Developing a drug beyond a certain stage is based on a marketing plan. At a strategic point in the development process, a pharmaceutical company must decide whether to invest millions of dollars in advanced pharmacological studies and eventually clinical trials. Numerous considerations come into play in making such a decision. One of those is whether the drug can reach a sales level of about $500 million within two to three years of introduction. Many potential new drugs are lost to further development at that decision gate. If the projected sales are not large enough, the compound will simply not be developed as a potential clinical entity. Consequently, unless these compounds are “rescued” as orphan drugs for development, and very few are, they will remain inaccessible (since they are patented and therefore must be licensed to be developed further) to the majority in the global health care system for whom they may be both useful and affordable. With this very brief background, it is possible to imagine that as natural product scientists we are now deeply lost in the maze of drug discovery. That, with the continuous advances in chemical and robotic processing technology and the biotechnology of assay system development that we already may be too late to have an impact on the discovery process. The dedication (and success!) of the National Cancer Institute to bring natural products to clinical trials stands as a beacon, which the pharmaceutical industry has chosen to ignore for other disease states. With all of these issues, including the evolving situation with respect to access to the biome, it is tempting to think along the lines of completely divorcing the plant sciences from natural product drug discovery and development. As

《天然药物化学》课程参考文献（天然药物研究与开发）Natural products in drug discovery – Creating a new vision