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1351/pac200577010007 © 2005 IUPAC
Biodiversity: A continuing source of novel drug leads*
Gordon M. Cragg‡ and David J. Newman
Natural Products Branch, Developmental Therapeutics Program, 206 Fairview Center, NCI-Frederick, P.O. Box B, Frederick, MD 21702-1201, USA Abstract: Nature has been a source of medicinal agents for thousands of years and continues to be an abundant source of novel chemotypes and pharmacophores. With only 5 to 15 % of the approximately 250 000 species of higher plants systematically investigated, and the potential of the marine environment barely tapped, these areas will remain a rich source of novel bioactive compounds. Less than 1 % of bacterial and 5 % of fungal species are currently known, and the potential of novel microbial sources, particularly those found in extreme environments, seems unbounded. To these natural sources can be added the potential to investigate the rational design of novel structure types within certain classes of microbial metabolites through genetic engineering. It is apparent that Nature can provide the novel chemical scaffolds for elaboration by combinatorial approaches (chemical and biochemical), thus leading to agents that have been optimized on the basis of their pharmacological activities. The proven natural product drug discovery track record, coupled with the continuing threat to biodiversity through the destruction of terrestrial and marine ecosystems and the current low number of new chemical entities in pharmaceutical industry pipelines, provides a compelling argument in favor of expanded multidisciplinary and international collaboration in the exploration of Nature as a source of novel leads for the development of drugs and other valuable bioactive agents. BIODIVERSITY: MEDICINALS FOR THE MILLENNIA Recorded history Throughout the ages, humans have relied on Nature for their basic needs for the production of foodstuffs, shelters, clothing, means of transportation, fertilizers, flavors and fragrances, and, not least, medicines. Plants have formed the basis of sophisticated traditional medicine systems that have been in existence for thousands of years. The first records, written on clay tablets in cuneiform, are from Mesopotamia and date from about 2600 B.C.; among the substances they used were oils of Cedrus species (cedar) and Cupressus sempervirens (cypress), Glycyrrhiza glabra (licorice), Commiphora species (myrrh), and Papaver somniferum (poppy juice), all of which are still in use today for the treatment of ailments ranging from coughs and colds to parasitic infections and inflammation. Egyptian medicine dates from about 2900 B.C., but the best known Egyptian pharmaceutical record is the Ebers Papyrus dating from 1500 B.C.; this documents some 700 drugs (mostly plants), and includes formulas, such as gargles, snuffs, poultices, infusions, pills, and ointments, with beer, milk, wine, and honey being commonly used as vehicles. The Chinese Materia Medica has been extensively documented over
*Paper based on a presentation at the 24th International Symposium on the Chemistry of Natural Products and the 4th International Congress on Biodiversity, held jointly in Delhi, India, 26–31 January 2004. Other presentations are published in this issue, pp. 1–344. ‡Corresponding author: Fax: 301-846-5387; E-mail: email@example.com
J.nih. Pure and Applied Chemistry 77. mainly residing in developed countries.). 1). a Greek physician (100 A. containing 52 prescriptions). and this system formed the basis for the primary text of Tibetan Medicine. © 2005 IUPAC. artemisinin and its derivatives. (Susruta and Charaka). was reported in 1820 by the French pharmacists. and was first introduced into Europe in the early 1600s for the treatment of malaria. who practiced and taught pharmacy and medicine in Rome. sometimes containing dozens of ingredients (“galenicals”). and use of medicinal herbs. quinine (Fig. Dioscorides. and the Tang Herbal (659 A. The use of plants in the traditional medicine systems of many other cultures has been extensively documented [4–9]. Plant products also play an important role in the health care systems of the remaining 20 % of the population. which have been used for thousands of years in countries such as China  and India . M.C.D. from the bark of Cinchona species (e. In addition. Avicenna.C..S. Ireland. The bark had long been used by indigenous groups in the Amazon region for the treatment of fevers. published no less than 30 books on these subjects. . Quinine formed the basis for the synthesis of the commonly used antimalarial drugs. In the ancient Western world. 1). and noted the ability to change their characteristics through cultivation.gov/hmd/medieval/arabic. and the Persian pharmacist. National Institutes of Health (NIH) at <www. but it was the Arabs who were responsible for the preservation of much of the Greco-Roman expertise. and for expanding it to include the use of their own resources. A comprehensive review of the history of medicine may be found on the NLM History of Medicine homepage at <www. 7–24 . Analysis of data on prescriptions dispensed from community pharmacies in the United States from 1959 to 1980 indicates that about 25 % contained plant extracts or active principles derived from higher plants.). traditional medicine. and poet. artemether and arteether (Fig. U.gov/hmd/hmd. 74 % were discovered as a result of chemical studies directed at the isolation of the active substances from plants used in traditional medicine.html>.8 G. (Wu Shi Er Bing Fang.nlm. officinalis). The philosopher and natural scientist. can be considered as important drugs currently in use in one or more countries . Information on this and other Arabic works may be found on the Web site of the National Library of Medicine (NLM). Caventou and Pelletier. and at least 119 chemical substances.nih. another plant long used in the treatment of fevers in traditional Chinese medicine. physician. with the first record dating from about 1100 B. the monasteries in countries such as England. With the emergence of resistance to these drugs in many tropical regions. and drug discovery As mentioned above. France.html>. and Galen (130–200 A. 850 drugs).D. C. CRAGG AND D. in his History of Plants. Plant sources. and is well known for his complex prescriptions and formulas used in compounding drugs. documentation of the Indian Ayurvedic system dates from about 1000 B. effective against resistant strains . recorded the collection.. These plantbased systems continue to play an essential role in health care. dealt with the medicinal qualities of herbs.C.C. During the Dark and Middle Ages (fifth to twelfth centuries A. plants have formed the basis for traditional medicine systems. the use of so-called complementary or alternative herbal products has expanded in recent decades . Gyu-zhi (Four Tantras) translated from Sanskrit during the eighth century A.D. storage. The isolation of the antimalarial drug. derived from 90 plant species. and Germany preserved the remnants of this Western knowledge. the Greeks contributed substantially to the rational development of the use of herbal drugs. The Arabs were the first to establish privately owned drug stores in the eighth century. together with Chinese and Indian herbs unknown to the Greco-Roman world. NEWMAN the centuries. contributed much to the sciences of pharmacy and medicine through works such as Canon Medicinae. regarded as “the final codification of all Greco-Roman medicine”. and it has been estimated by the World Health Organization that approximately 80 % of the world’s inhabitants rely mainly on traditional medicines for their primary health care . 365 drugs). during his travels with Roman armies. Theophrastus (~300 B.D. Likewise. Of these 119 drugs.D. Artemisia annua (Quinhaosu).nlm.g. chloroquine and mefloquine (Fig.).). 1). has yielded the agents. philosopher.. followed by works such as the Shennong Herbal (~100 B.
isolated from the Madagascar periwinkle. as a specific disease entity. brevifo© 2005 IUPAC. may be considered being more closely linked to a plant originally used for the treatment of cancer.Biodiversity: A continuing source of novel drug leads 9 Fig. a plant long used in traditional Chinese medicine. tubocurarine. Fig. epipodophyllotoxin. roseus was used by various cultures for the treatment of diabetes. used in ancient Mesopotamia (vide infra). collected in Washington state as part of a random collection program by the U. 1 Plant-derived antimalarial agents. among the best known are the so-called vinca alkaloids. etoposide and teniposide. These plants possess a long history of medicinal use by early American and Asian cultures. The two clinically active agents. first isolated in 1887 from Ephedra sinica (Ma Huang). and vinblastine and vincristine were first discovered during an investigation of the plant as a source of potential oral hypoglycemic agents. Of the plantderived anticancer drugs in clinical use. reserpine. curare . isolated from Chondrodendron and Curarea species used by indigenous groups in the Amazon as the basis for the arrow poison. and the muscle relaxant. morphine. though many of the claims for the efficacy of such treatment should be viewed with some skepticism because cancer. Catharanthus roseus. may be indirectly attributed to the observation of an unrelated medicinal use of the source plant. Papaver somniferum. Their discovery. including the treatment of skin cancers and warts . Paclitaxel (Taxol®. The analgesic. 2) initially was isolated from the bark of Taxus brevifolia.S. 2). isolated from Rauwolfia serpentina used in Ayurvedic medicine for the treatment of snakebite and other ailments . which are semisynthetic derivatives of the natural product.S. therefore. laid the basis for alkaloid chemistry and the development of a range of highly effective analgesic agents . National Cancer Institute (NCI) . Epipodophyllotoxin is an isomer of podophyllotoxin. isolated in 1816 by the German pharmacist. 7–24 . salbutamol and salmetrol. More recent additions to the armamentarium of plant-derived chemotherapeutic agents are the taxanes and camptothecins. The use of various parts of T. Department of Agriculture for the U. is likely to be poorly defined in terms of folklore and traditional medicine . Plants have a long history of use in the treatment of cancer . ephedrine. Serturner. from the opium poppy. Pure and Applied Chemistry 77. Other significant drugs developed from traditional medicinal plants include: the antihypertensive agent. and the basis for the synthesis of the anti-asthma agents (beta agonists). vinblastine and vincristine (Fig. C. which was isolated as the active antitumor agent from the roots of various species of the genus Podophyllum.
2). proteins.g. Likewise. Camptotheca acuminata  Camptothecin (as its sodium salt) was in clinical trials at NCI in the 1970s. and the ready semisynthetic conversion of the relatively abundant baccatins to paclitaxel. rohitukine (Fig. and active paclitaxel analogs. from the Chinese tree Cephalotaxus harringtonia var. Pure and Applied Chemistry 77. baccata are used in the traditional Asiatic Indian (Ayurvedic) medicine system . renewable natural source of this important class of drugs. isolated from the Chinese ornamental tree. A significant number of compounds based upon the combretastatin skeleton have been synthesized in the search for more effective anticancer agents . but was dropped because of severe bladder toxicity. derived from Combretum caffrum. combretastatin A-4 phosphate (Fig. the clinically active agents. A significant number of plant-sourced agents are still in clinical trials for the treatment of cancer. CRAGG AND D. are a family of stilbenes which act as anti-angiogenic agents. or pathways .22]. topotecan (hycamptamine) and irinotecan (CPT-11). while the leaves of T. Some are being investigated as direct cytotoxins. was made by the Indian subsidiary of Hoechst (now Aventis) following the isolation and synthesis of the plant-derived natural product. whereas others are being studied from the aspect of their potential role as inhibitors of particular cell cycle enzymes. Flavopiridol (Fig. The combretastatins. J. has shown promise in early clinical trials and is currently in Phase II [19. Paclitaxel. occurs in the leaves of various Taxus species.10 G. 7–24 . but is reported as being used in China as an anticancer agent . M. Homoharringtonine. baccata) by several Native American tribes for the treatment of some noncancerous conditions has been reported . are semisynthetically derived from camptothecin. 2). 2 Plant-derived anticancer agents. © 2005 IUPAC. such as docetaxel .. with one reported use in the treatment of cancer . 2). canadensis. and a water-soluble analog. NEWMAN Fig. has provided a major. particularly paclitaxel and cis-platinum . drupacea (Sieb and Zucc). is still in clinical trials against various leukemias in the West. along with several key precursors (the baccatins). causing vascular shutdown in tumors and resulting in tumor necrosis. and is currently in Phase III clinical trials both as a single agent and in combination with other agents. lia and other Taxus species (e.
and the observation of the broad therapeutic use of this agent in the 1940s. Several plant extracts showed significant activity. such as mevastatin (compactin) and lovastatin (from Penicillium species) (Fig. possibly the most potent antitumor compound to be approved for clinical use. streptozocin and deoxycoformycin . The epothilones (Fig. idarubicin. which include members of the anthracycline. 4). the cyclosporins. Of these. along with other organizations. languished for a number of years as it was just too toxic to pursue. and aureolic acid families . and the active compounds were isolated. isolated from Homalanthus nutans [25. These include: antibacterial agents. All were isolated from various Streptomyces species. immunosuppressive agents. Penicillium notatum. Pure and Applied Chemistry 77. isolated from the Myxomycetales (gliding bacteria) are in clinical development. aminoglycosides. 3 Plant-derived anti-HIV agents. 3). and recently has been approved for clinical use as Mylotarg®. © 2005 IUPAC. doxorubicin.org/programmes/socioeco/benefit/case-studies. Antitumor antibiotics are among the most important of the cancer chemotherapeutic agents. thereby reducing the systemic toxicity. ushered in a new era in medicine. bleomycin. Calicheamicin (Fig. cholesterol-lowering agents.30]. in spite of its exquisite subpicomolar level activity [29. the compound is carried to the site where needed and released in situ.26] have progressed into clinical and preclinical development. Case Study 19]. Over 60 000 extracts of marine and plant origin were tested in vitro against lymphoblastic cells infected with HIV-1. the peptolides exemplified by d-actinomycin.asp>. see also Convention on Biological Diversity. respectively (Fig. cephalosporins (from Cephalosporium cryptosporium). <http://www. and microorganisms have proved to be a prolific source of structurally diverse bioactive metabolites which have yielded some of the most important products of the pharmaceutical industry. the calanolides. Microbial sources and the Golden Age of Antibiotics The serendipitous discovery of penicillin from the filamentous fungus. the NCI. and are of great interest as potential antitumor agents due to their mechanism of action being the same as that of paclitaxel (vide infra) though having at first glimpse. by Fleming in 1929. and prostratin. and anthelmintics and antiparasitic drugs. mithramycin. daunomycin itself. such as the penicillins (from Penicillium species). isolated from Calophyllum species [24. and rapamycin (from Streptomyces species). Fig.biodiv. mitomycin. such as the ivermectins (from Streptomyces species) . The compound has been linked to a specific monoclonal antibody directed against chronic myologenous leukemia. 4). This discovery promoted the intensive investigation of nature as a source of novel bioactive agents. but not its innate activity . as were two other clinically active agents. the mitosanes such as mitomycin C. and the glycosylated anthracenone. the so-called Golden Age of Antibiotics . quite a different topology . tetracyclines. such as the fungal metabolites.Biodiversity: A continuing source of novel drug leads 11 With the emergence of the AIDS pandemic in the 1980s. and other polyketides of many structural types (from the Actinomycetales). and epirubicin. actinomycin. Clinically useful agents from these families are the daunomycin-related agents. the glycopeptidic bleomycins A2 and B2 (Blenoxane®). 7–24 . 4). has been involved in the exploration of nature as a source of potential agents for the treatment of AIDS and associated opportunistic infections. Thus.
M. represented by 17-allylamino-geldanamycin (17-AAG) (Fig. 4) which is also in Phase I trials [34. the collection of marine organisms was limited to those obtainable by skin diving. depths from approximately 3 to 35 meters became routinely attainable. represented by staurosporine and its simple derivative UCN-01 (Fig. Prior to the development of reliable scuba diving techniques some 40 years ago. These disadvantages can be partially over© 2005 IUPAC. Pure and Applied Chemistry 77. with eight being exclusively aquatic. mainly marine . Deep water collections can be made by dredging or trawling. 4). 4 Microbial-derived drugs. J.12 G. Marine sources While marine organisms do not have a significant history of use in traditional medicine.33]. and the marine environment has been increasingly explored as a source of novel bioactive agents. the ancient Phoenicians employed a chemical secretion from marine mollusks to produce purple dyes for woolen cloth. covering more than 70 % of the earth’s surface. 7–24 . represent an enormous resource for the discovery of potential chemotherapeutic agents. All but two of the 28 major animal phyla are represented in aquatic environments. and the geldanamycin derivatives. such as environmental damage and nonselective sampling.35]. The world’s oceans. Other interesting microbially derived chemotypes include the indolocarboxazoles. which is in Phase I clinical trials [21. Subsequently. NEWMAN Fig. and seaweeds have long been used to fertilize the soil. but these methods suffer from disadvantages. CRAGG AND D.
Sponges are traditionally a rich source of bioactive compounds in a variety of pharmacological screens . a linear depsipeptide which was shown to be a tubulin interactive agent. many derivatives of the dolastatins have been synthesized with TZT-1027 (Auristatin PE or Soblidotin) now in Phase II clinical trials in Europe. and the United States . which have provided models for the synthesis of novel painkillers (e. The cryptophycins are metabolites isolated from a terrestrial cyanophyte (Nostoc sp. isolated from Jaspis cf. responses in Phase I trials have been reported . isolated from the Caribbean sponge. Halichondria okadai. As a result of the synthetic processes. cisplatin. isolated from the Hawaian mollusk. and spongothymidine. Phakellia carteri from the Eastern Indian Ocean. These compounds were found to possess antiviral activity. Bugula neritina . together with Ara-A as an antiviral agent. New Zealand . isolated from the Caribbean tunicate. off the east coast of South Island. Other marine-derived compounds currently in clinical trials against cancer include ecteinascidin 743. and from Lissodendoryx sp. a synthetic analog of bengamide A. 7–24 . with more than 20 being completed at both the Phase I and Phase II levels . collected off the New England coast . The sea hare. The first notable discovery of biologically active compounds from marine sources was the serendipitous isolation of the C-nucleosides. and progressed through to Phase II trials as a single agent. is the source of more than 15 cytotoxic cyclic and linear peptides. Pure and Applied Chemistry 77. aplidine. HTI-286. Elysia rufescens [47. which was originally isolated in 1985 from the Japanese sponge. Japan. kahalalide F. the dolastatins.48]. no compound isolated from a marine source has advanced to commercial use as a chemotherapeutic agent.) and an Okinawan sponge. As yet. The systematic investigation of marine environments as sources of novel biologically active agents only began in earnest in the mid-1970s.Biodiversity: A continuing source of novel drug leads 13 come by use of manned submersibles or remotely operated vehicles (ROVs). dolastatin 10. Hemiasterella minor . paclitaxel.g. spongouridine. Ziconotide®) which currently is in a pivotal Phase III trial . cryptophycin 52 (LY355703). 5). coraciae. 5)  originally isolated from a South African sponge.. though several are in various phases of clinical development as potential anticancer agents.. isolated from the common dogfish shark. Squalus acanthias. discodermolide (Fig. Due to its potency and mechanism of action. administration as a single agent is probably not the optimal usage for this agent. but were dropped due to lack of efficacy . These include the polyhydroxylated lactone. Dysidea arenaria. and a synthetic analog (E7389) of halichondrin B (Fig. spisulosine. 5) . Trididemnum solidum . Discodermia dissoluta . fludarabine. and a semisynthetic derivative. and LAF-389. isolated from the bryozoan. progressed to Phase II clinical trials. However. Cryptotheca crypta. entered Phase I clinical trials in the 1990s. the high cost of these forms of collecting precludes their extensive use in routine collections. squalamine. Spisula polynyma . and synthetic analog studies eventually led to the development of cytosine arabinoside (Ara-C) as a clinically useful anticancer agent approximately 15 years later . Ecteinascidia turbinata . bryostatin 1 has been in more than 80 human clinical trials. The extremely potent venoms (conatoxins) of predatory cone snails (Conus species) have yielded complex mixtures of small peptides (6–40 amino acids). The most prominent of these is bryostatin 1 (Fig. © 2005 IUPAC. from the Caribbean sponge. many of which belong to totally novel chemical classes not found in terrestrial sources . and soon thereafter from a Papua New Guinea sponge from the genus Cymbastela. but has been dropped due to lack of significant activity. and a number of sponge-derived agents are in clinical development as potential anticancer agents . and subsequently from Axinella sp. etc. isolated from the marine clam. Dolabella auricularia from the Indian Ocean. and when combined with cytotoxic drugs such as the vinca alkaloids. however. 5). but was withdrawn in 2002 . These studies have clearly demonstrated that the marine environment is a rich source of bioactive compounds. the dehydro analog of didemnin B. To date. Girolline isolated from Pseudaxinyssa cantharella. from the Western Pacific. a synthetic analog of hemiasterlin (Fig. . in the early 1950s. isolated from the Caribbean ascidian. advanced into clinical trials.
5 Marine-derived anticancer drugs. NEWMAN Fig. captopril and enalapril . CURRENT STATUS OF DRUG DISCOVERY The interest in nature as a source of potential chemotherapeutic agents continues . Bothrops jaracaca. has led to the development of a novel class of painkillers . Other sources Teprotide. CRAGG AND D. isolated from the venom of the pit viper. Pure and Applied Chemistry 77. used in the treatment of cardiovascular disease. An analysis of natural products as sources of new drugs over the period 1981–2002 indicates that 67 % of the 877 © 2005 IUPAC. Epipedobates tricolor. M. J.14 G. isolated from the skin of the poisonous frog. led to the design and synthesis of the ACE inhibitors. 7–24 . while epibatidine.
but 16. the statins. a vital role in the drug discovery process. In the area of anti-infectives (antibacterial. or mimic (i. and many source country organizations and scientists are well placed to take a leadership role in this area. also known as new chemical entities hit a 20-year low of 37 in 2001 . GMDs) derived from microbes separated from environmental samples (sea water and soil) has recently been published .. Another vast untapped resource is that of the insect world. Use of “nutrient-sparse” media under conditions simulating the original natural environment. it is estimated that only 5–15 % of the approximately 250 000 species of higher plants have been systematically investigated. close to 70 % are naturally derived or inspired. and -viral). In recent years. new chemical entities (NCEs) are formally synthetic. Thus. In a report released by the American Academy of Microbiology entitled “The Microbial World: Foundation of the Biosphere”. microbiologists were greatly limited in their study of natural microbial ecosystems due to an inability to cultivate most naturally occurring microorganisms. Unexplored potential of microbial diversity Until recently.inbio. Further evidence of this drop in productivity is evident from the report that only 16 new drug applications had been received by the U. The marine environment as a source of novel drugs has already been discussed.” It is clear that Nature has played. however. but the potential of this area remains virtually unexplored. “We would not have the top-selling drug class today. in collaboration with academia and industry (<http://www.S. the whole area of immunosuppressives. 12 % are actually modeled on a natural product inhibitor of the molecular target of interest.ac. Furthermore. and organizations. no mention was made.cr/papers/insectoscr/Insectcr.org>) in Costa Rica. Recently. and the number of new active substances.inbio. This downturn has been attributed in part to disruption of laboratory activities by the surge in company mergers and acquisitions.html>). such as the Instituto Nacional de Biodiversidad (INBio. of a contributing factor being the de-emphasis by many companies of the “tried and true” exploration of nature as the source of novel leads for drug development. As stated by one authority. are investigating the potential of this and other natural resources. down from 24 the previous year . Pure and Applied Chemistry 77. and will continue to play. 7–24 . <http://www. while in the cancer treatment area 67 % are in this category. -fungal. there has been a steady decline in the output of the R&D programs of the pharmaceutical industry. it is estimated that “less than 1 % of bacterial species and less than 5 % on fungal species are currently known”.4 % correspond to synthetic molecules containing pharmacophores derived directly from natural products . BIODIVERSITY AND THE CONTINUED GENERATION OF MOLECULAR DIVERSITY Expanded exploration of classical environments Despite the intensive investigation of terrestrial flora. The potential of large areas of tropical rainforests remains virtually untapped. the whole field of angiotensin antagonists and angiotensin-converting-enzyme inhibitors. © 2005 IUPAC. Improved culturing procedures Recent developments of procedures for cultivating and identifying microorganisms will aid microbiologists in their assessment of the earth’s full range of microbial diversity. chemically and pharmacologically . there have been reports of a rekindling of interest in “rediscovering natural products” . only 39 % of the 877 NCEs can be classified as truly synthetic in origin . and the FDA over-caution in the drug approval process . competitively inhibit) the endogenous substrate of the active site. -parasitic. Imagine all of those drugs not being available to physicians or patients today.e. such as ATP. nor most of the anticancer and antibacterial drugs. Food and Drug Administration (FDA) in 2001. and recent evidence indicates that millions of microbial species remain undiscovered . Application of a technique for the massive parallel cultivation of gel-encapsulated single cells (gel micro-droplets.Biodiversity: A continuing source of novel drug leads 15 small molecule. the mounting costs of drug development.
diversa. 6 Drugs derived from endophytic fungi. kakadumycins. coli provided access to reasonable quantities of the small molecule antibiotics of interest. alkalophiles (alkaline lakes).and thermophiles (deep-sea vents) . Pantoea agglomerans . thereby preventing overgrowth by the fast-growing “microbial weeds”.com>). the endophytic microbes that reside in the tissues between living plant cells have received scant attention. such as acidophiles (acidic sulfurous hot springs). Valuable products and information are certain to result from the cloning and understanding of the novel genes that will be discovered through these processes. CRAGG AND D. 7–24 . procedures based on the extraction of nucleic acids (the metagenome) from environmental samples permit the identification of uncultured microorganisms through the isolation and sequencing of ribosomal RNA or rDNA (genes encoding for rRNA). Pure and Applied Chemistry 77. isolated from the endophytic © 2005 IUPAC. expression of a genomic DNA library from P. A recent example of heterologous expression of genomic DNA is the production of the antibiotic. Extraction of environmental samples In addition. Heterologous expression of gene clusters encoding the enzymes involved in biosynthetic pathways in viable host organisms. and the methods may be applied to other habitats. such as the microflora of insects and marine animals . and psychrophiles (Arctic and Antarctic waters. M. and the culturing and scale-up cultivation of previously uncultivated microbes.16 G. Extremophiles Extreme habitats harbor a host of extremophilic microbes (extremophiles). Among the new bioactive molecules discovered are: novel wide-spectrum antibiotics. J. While investigations thus far have focused on the isolation of thermophilic and hyperthermophilic enzymes . samples from soils are currently being investigated. there are reports of useful enzymes being isolated from other extreme habitats (<www. halophiles (salt lakes).and fastgrowing microorganisms”. alpine lakes) . piezo (baro). and limited studies have revealed an interesting realm of novel chemistry . such as Escherichia coli. These extreme environments will also undoubtedly yield novel bioactive chemotypes. Fig. 6). The relationship established between the endophytes and their host plants may vary from symbiotic to pathogenic. Endophytes While plants have received extensive study as sources of bioactive metabolites. however. NEWMAN “permits the simultaneous and relatively non-competitive growth of both slow. Low titers and the complexity of the mixture of metabolites produced. This has resulted in the identification of previously undetected species (using 16S rRNA gene sequencing). should permit the production of novel metabolites produced from as yet uncultured microbes. agglomerans in E. from the bacterium. pantocin A (Fig. made production of pantocin A by the microbe grown in liquid culture impractical.
currently undergoing clinical trials as a potential anticancer agent. immunosuppressive compounds produced by Fusarium subglutinans. an endophyte of T. 7–24 . As Dr. salinosporamide A (Fig. 6).S. Combinatorial biosynthesis Advances in the understanding of bacterial aromatic polyketide biosynthesis have led to the identification of multifunctional polyketide synthase enzymes (PKSs) responsible for the construction of polyketide backbones of defined chain lengths. Based on combined culture and phylogenetic approaches. in the epoxidation of epothilone D to epothilone B has been demonstrated. 4). the degree and regiospecificity of ketoreduction. and is the des-epoxy precursor of epothilone B (Fig. In the process of total synthesis. Members of the genus are ubiquitous and are found in sediments on tropical ocean bottoms and in more shallow waters. Marine sediments Recent research has revealed that deep ocean sediments are a valuable source of new actinomycete bacteria that are unique to the marine environment. doxorubicin. in some instances. the first truly marine actinomycete genus named Salinospora has been described . a very potent proteasome inhibitor (IC50 = 1. Since polyketides constitute a large number of structurally diverse natural products exhibiting a broad range of biological activities (e. tetracyclines. means to clean polluted environments.. and the regiospecificity of cyclizations and aromatizations. and to developments in chiral catalytic reactions .Biodiversity: A continuing source of novel drug leads 17 streptomycete associated with the fern-leafed grevillea (Grevillea pteridifolia) from the Northern Territory of Australia . ambuic acid (Fig. the potential for generating novel molecules with enhanced known bioactivities. and subglutinols A and B. More recently. the efforts of some groups have been focused on the synthesis and modification of drugs that are difficult to isolate in sufficient quantities for development. often reaching concentrations up to 104 per cc of sediment. Rita Colwell. A notable example is that of the marine-derived antitumor © 2005 IUPAC. and better ways to manufacture products used daily in modern society” . this has led to the synthesis of simpler analogs having similar or better activity. They can be cultured using the appropriate selective isolation techniques. an antifungal agent which has been recently described from several isolates of Pestalotiopsis microspora.78].3 nM) . 4). Director of the U. has stated: “Hiding within the as-yet undiscovered microorganisms are cures for diseases. Epothilone D is the most active of the epothilone series isolated from the myxobacterium. National Science Foundation. together with the genes encoding for the enzymes [73–75]. Sorangium cellulosum. The isolation and sequencing of the polyketide gene cluster producing epothilone B from two S. wilfordii . cellulosum strains has been reported [77. or even novel bioactivities.80]. 5). and has led to the discovery of many novel reactions. appears to be high . They also appear on the surfaces of numerous marine plants and animals. encoding cytochrome P450. epoK. and. it is often possible to determine the essential features of the molecule necessary for activity (the pharmacophore). new food sources. Total synthesis of natural products The total synthesis of complex natural products has long posed challenges to the top synthetic chemistry groups worldwide. and significant antibiotic and cytotoxic activity has been observed. commenting on the importance of exploration and conservation of microbial diversity. A recent example of the power of this technique when applied to natural products is the development of an efficient method for scale-up production of epothilone D (Fig. Heterologous expression of the gene cluster minus the epoK into Myxococcus xanthus resulted in largescale production of crystalline epothilone D [79. and avermectin). Pure and Applied Chemistry 77. leading to the isolation of a very potent cytotoxin. found in many of the world’s rainforests . and the role of the last gene in the cluster.g.
M. 7). The importance of natural products as leads for combinatorial synthetic approaches is embodied in the concept of “privileged structures” advanced by Nicolaou et al. which have permitted high-throughput parallel approaches to the synthesis of very large libraries of millions of compounds. but were intrinsically more chemically stable. 5). Over the last few years. While there are claims that new leads are being found . is permitting the determination of the structures of many of the proteins associated with disease processes. impractically large. Combinatorial chemistry is a technique originally developed for the synthesis of large chemical libraries for high-throughput screening against such targets . Pure and Applied Chemistry 77. but thus far none of the analogs has been reported to surpass epothilone B in its potency against tumor cells. Combinatorial chemistry and natural products The analysis of the human genome. 4) by several groups has permitted the preparation of a large number of designed analogs and detailed structure–activity studies. ). and linkers. reagents. 7–24 . such as solid-phase synthesis and new immobilization strategies involving novel resins. thereby enabling structure–activity relationships to be probed. The synthesis of the epothilones (Fig. These studies have identified desirable modifications.b]. can also be applied to the generation of large numbers of analogs for structure–activity studies. as well as advances in the description of the genomes of pathogenic microbes and parasites . J. and structurally simplistic” . with another 8000 structures identified through the inclusion of a slight modification of the search (see Fig. CRAGG AND D. with some of the earlier libraries being described as “poorly designed. (NSC 707389/E7389) (Fig. The synthesis of natural product-like libraries is exemplified by the work of the Schreiber group who have combined the simultaneous reaction of maximal combinations of sets of natural product-like core structures (“latent intermediates”) with peripheral groups (“skeletal information elements”) in the synthesis of libraries of over 1000 compounds bearing significant structural and chiral diversity [88a. In 1992. Nicolaou’s group then proceeded to develop the nec© 2005 IUPAC.18 G. A search of the literature yielded nearly 4000 2. 4). well-characterized compounds” with “a particularly strong move toward the synthesis of complex natural-product-like compounds—molecules that bear a close structural resemblance to approved natural-product-based drugs”.84]. Two of these agents were subsequently evaluated by NCI in conjunction with the Eisai Research Institute in the United States. which have been reviewed . particularly smaller molecules that maintained the biological activity. NEWMAN agent. using an active natural product as the central scaffold. This has led to the development of robotic systems and tools. the declining numbers of new NCEs  indicate that the use of de novo combinatorial chemistry approaches to drug discovery over the past decade have been disappointing. is now in Phase I clinical trials [83. The combinatorial approach. the synthesis of both halichondrin B and norhalichondrin B was reported . solid-phase synthesis of combinatorial libraries was used to probe regions of the molecule important to retention or improvement of activity . which might eventually lead to more suitable candidates for drug development. and one of the compounds. detailed analyses of active natural product skeletons have led to the identification of relatively simple key precursor molecules which form the building blocks for use in combinatorial synthetic schemes that have produced numbers of potent molecules. the so-called parallel synthetic approach . Thus. due to the substitution of a ketone for the ester linkage in the macrolide ring. in the study of the structure–activity relationships of the epothilones (Fig. halichondrin B (Fig. As stated in the recent article . With the development of these new molecular targets. there is an increasing demand for novel molecular diversity for screening. [90–92]. which presumably have undergone evolutionary selection over time. and stated as follows: “We were particularly intrigued by the possibility that using scaffolds of natural origin. “an initial emphasis on creating mixtures of very large numbers of compounds has largely given way in industry to a more measured approach based on arrays of fewer. 5) mentioned earlier. might confer favorable bioactivities and bioavailabilities to library members”.2-dimethyl-2H-benzopyran moieties (Fig. and the synthetic schemes were utilized to synthesize a large number of variants of halichondrin B. 2 in ref.
Another conjugate. calicheamicin. These factors have resulted in the demise of a number of pure natural products. The first FDA-approved. they have limited solubility in aqueous solvents and exhibit narrow therapeutic indices. An alternative approach to utilizing such agents is to investigate their potential as warheads attached to monoclonal antibodies specifically targeted to epitopes on tumors of interest . This technique has been applied to the modification of the natural product galanthamine (Fig. Fig. produced by the coupling of DM1. 8). at least in the area of cancer chemotherapy. essary solid-phase synthetic methods by modifying a reagent that they had reported in the literature a couple of years earlier. 7 Privileged structures. huN901-DM1. such as bruceantin and maytansine. 7–24 . Application of this methodology has led to the identification and subsequent optimization of benzopyrans with a cyanostilbene substitution that are effective against vancomycin-resistance bacteria (Fig. The only other known agents to do this were based on the microbial product. is that although many are generally very potent.Biodiversity: A continuing source of novel drug leads 19 Fig. Targeting natural products A recurring liability of natural products. as promising leads. The same maytansinoid derivative linked to a different anti© 2005 IUPAC. brefeldin. that inhibited this process. Pure and Applied Chemistry 77. is being developed for the treatment of small-cell lung cancer . as the warhead was mentioned earlier (vide infra) . a cytotoxic agent derived from maytansine. a polystyrene-based selenenyl bromide resin . 8)  using combinatorial techniques. and then assaying the products using a novel screen that looked for inhibition of protein trafficking in the Golgi apparatus. which they named secramine (Fig. 8 Application of chemical genetics. The approach of probing complex biological processes by altering the function of proteins through binding with small molecules has been called chemical genetics . natural product-based example (Mylotarg®). with a monoclonal antibody targeting small-cell lung cancer cells. using the microbial metabolite. They identified a modified nucleus derived from galanthamine. 7) . an entirely different structure in a formal sense.
fic. and clinical trials.nih. 6.S. U. and pharmaceutical companies (<http://www. National Institutes of Health (NIH. known as SB408075. M. M. 3. D. H. is currently in Phase I clinical trials in the United States . CRAGG AND D. toxicology.htm>). Fallarino. and development and economic development. Arvigo and M. 270 Plantas Medicinales Iberoamericanas. Medicinal Plants of the West Indies.cyted. Boca Raton.S. Gupta. R. academic groups. 8. Philippines.-M. Uzbekistan. Handbook of African Medicinal Plants. After injection and localization of an antibody-enzyme conjugate at the tumor. Papua New Guinea. Singapore (1986). Addition of a sugar to the polymer enables specific targeting for the hepatocyte. Bogota. © 2005 IUPAC. it is converted to the cytotoxin by the enzyme localized at the tumor site. and microbiology. A similar program is supported by the NCI through its National Cooperative Drug Discovery Group (NCDDG) program . Jain. such as through the International Cooperative Biodiversity Group (ICBG) program coordinated by the U. REFERENCES 1. M. K. Kapoor.nih. <http://www. Ayensu. Reference Publications.html>). a nontoxic prodrug is administered. provides further potential for the application of potent natural products to cancer treatment . Current programs involve collaboration between U. J.org>). Consideration may be given to establishing collaborative programs between qualified institutions on a regional basis. M. Twin Lakes (1993). Another strategy of interest is the use of antibodies as vectors for enzymes capable of activating a nontoxic drug precursor (prodrug) to a potent cytotoxic moiety. Algonac. E.gov/programs/icbg. P.gov/news/pr/dec2003/fic-16. World Scientific Publishing. Herbalgram 31. Samoa. opportunities exist for establishing collaborations with academia and industry in industrialized countries. Florida (1993). 7–24 . <http://www. NEWMAN body directed against the muc1 epitope in gastric cancers. Rainforest Remedies. called “antibody-directed enzyme prodrug therapy” (ADEPT). source country organizations in Costa Rica. 5. Algonac. Jamaica. S. Jordan. Pharmacology and Applications of Chinese Materia Medica. through cell and molecular biology and chemistry. Lotus Press. an organization comprising over 20 Central and South American countries and Portugal and Spain. 2. But. Pure and Applied Chemistry 77. Iwu. M. Boca Raton (1990).-H. marine biology. In addition. and while remaining innocuous to the normal tissues. CRC Press.20 G. Medicinal Plants of India. An excellent example of such regional collaboration is the Programa Iberoamericano de Ciencia Y Tecnologia Para el Desarrolo (CYTED. Panama. Laos. Colombia (1995). 4. having the goal of promoting international collaboration in scientific research. MI (1991). S. COLLABORATION: AN ESSENTIAL FACTOR IN DRUG DISCOVERY AND DEVELOPMENT The effective discovery and development of novel drugs requires close international and multidisciplinary collaboration. MI (1981). Balick. CRC Press. This involves disciplines ranging from botany. Another novel strategy for delivery of anticancer drugs to the tumor site involves the coupling of cytotoxins to water-soluble copolymers. drug discovery. 38–44 (1994). CRC Handbook of Ayurvedic Medicinal Plants. and this construct PK2 is currently in clinical trials . nongovernment organizations (NGOs) such as Conservation International. 7. Madagascar. CYTED. L. government agencies involved in conservation. Chang and P. Reference Publications. The continuing threat to biodiversity through the destruction of terrestrial and marine ecosystems lends urgency to the need to expand the collaborative exploration of these resources as a source of novel bioactive agents. to pharmacology.S. and Vietnam. P. This approach. Coupling of doxorubicin to an N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer produces the construct known as PK1 which is currently in Phase II trials .
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