Natural Products as a Foundation for Drug Discovery

John A. Beutler1

1 National Cancer Institute, Frederick, Maryland
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 9.11
DOI:  10.1002/0471141755.ph0911s46
Online Posting Date:  September, 2009
GO TO THE FULL TEXT: PDF or HTML at Wiley Online Library

Abstract

Natural products have provided chemical leads for the development of many drugs for diverse indications. While most U.S. pharmaceutical firms have reduced or eliminated their in‐house natural product groups, there is a renewed interest in this source of new chemical entities. Many of the reasons for the past decline in popularity of natural products are being addressed by the development of new techniques for screening and production. The aim of this unit is to review current strategies and techniques that increase the value of natural products as a source for novel drug candidates. Curr. Protoc. Pharmacol. 46:9.11.1‐9.11.21. © 2009 by John Wiley & Sons, Inc.

Keywords: natural products; drugs discovery; HTS

     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Table of Contents

  • History
  • Why has Pharma Minimized the Use of Natural Products as a Source for New Drugs?
  • Why Natural Products are Attractive for Drug Discovery
  • High‐Throughput Screening and Natural Products
  • Sourcing
  • Ethnobotany
  • Chemical Ecology
  • National Cancer Institute (NCI) Letter of Collection
  • Convention on Biodiversity
  • Techniques in Natural Products Drug Discovery
  • Recent Natural Product Drug Introductions
  • Which Companies are Still Conducting Natural Products Discovery?
  • Diversity‐Oriented Synthesis
  • Specialist Journals in Natural Product Science
  • Acknowledgements
  • Literature Cited
  • Figures
  • Tables
     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Materials

GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Figures

Videos

Literature Cited

Literature Cited
   Aicher, T.D., Buszek, K.R., Fang, F.G., Forsyth, C.J., Jung, S.H., Kishi, Y., Matelich, M.C., Scola, P.M., Spero, D.M., and Yoon, S.K. 1992. Total synthesis of halichondrin B and norhalichondrin B. J. Am. Chem. Soc. 114:3162‐3164.
   Akaike, N., Hattori, K., Oomura, Y., and Carpenter, D.O. 1985. Bicuculline and picrotoxin block γ‐aminobutyric acid‐gated Cl− conductance by different mechanisms. Experientia 41:70‐71.
   Anonymous. 2006. Protecting traditional knowledge: The San and Hoodia. Bull. World Health Organ. 84:345‐345.
   Arneric, S.P., Holladay, M., and Williams, M. 2007. Neuronal nicotinic receptors: A perspective on two decades of drug discovery research. Biochem. Pharmacol. 74:1092‐1101.
   Badio, B. and Daly, J.W. 1994. Epibatidine, a potent analgesic and nicotinic agonist. Mol. Pharmacol. 45:563‐569.
   Banskota, A.H., McAlpine, J.B., Sorensen, D., Ibrahim, A., Aouidate, M., Piraee, M., Alarco, A.M., Farnet, C.M., and Zazopoulos, E. 2006. Genomic analyses lead to novel secondary metabolites. Part 3. ECO‐0501, a novel antibacterial of a new class. J. Antibiotics 59:533‐542.
   Bento, E.S., Sant'Ana, A.E.G., Hawkes, G.E., Calixto, J.B., and Yunes, R.A. 2003. The structure of velutinoside A: A pregnane pentasaccharide from Mandevilla velutina. Tetrahedron Lett. 44:8335‐8337.
   Beutler, J.A., Karbon, E.W., Brubaker, A.N., Malik, R., Curtis, D.R., and Enna, S.J. 1985. Securinine alkaloids: A new class of GABA receptor antagonist. Brain Res. 330:135‐140.
   Beutler, J.A., Alvarado, A.B., McCloud, T.G., and Cragg, G.M. 1989. Distribution of phorbol ester bioactivity in the Euphorbiaceae. Phytother. Res. 3:188‐192.
   Beutler, J.A., Alvarado, A.B., Schaufelberger, D.E., Andrews, P., and McCloud, T.G. 1990. Dereplication of phorbol bioactives: Lyngbya majuscula and Croton cuneatus. J. Nat. Prod. 53:867‐874.
   Beutler, J.A., McKee, T.C., Fuller, R.W., Tischler, M., Cardellina, J.H. II, Snader, K.M., McCloud, T.G., and Boyd, M.R. 1993. Frequent occurrence of HIV‐inhibitory sulphated polysaccharides in marine invertebrates. Antiviral Chem. Chemother. 4:167‐172.
   Beutler, J.A., Kashman, Y., Tischler, M., Cardellina, J.H. II, Gray, G.N., Currens, M., Wall, M.E., Wani, M.C., and Boyd, M.R. 1995. A reinvestigation of Maprounea triterpenes. J. Nat. Prod. 58:1039‐1046.
   Beutler, J.A., Alvarado‐Lindner, A.B., and McCloud, T.G. 1996. Further studies on phorbol ester bioactivity in the Euphorbiaceae. Ann. Missouri Bot. Garden 83:530‐533.
   Bindseil, K.U., Jakupovic, J., Wolf, D., Lavayre, J., Leboul, J., and van der, P.D. 2001. Pure compound libraries; A new perspective for natural product based drug discovery. Drug Discov. Today 6:840‐847.
   Bladt, S. and Wagner, H. 2007. From the Zulu medicine to the European phytomedicine Umckaloabo. Phytomed. 14:2‐4.
   Blunt, J.W., Copp, B.R., Munro, M.H.G., Northcote, P.T., and Prinsep, M.R. 2004. Marine natural products. Nat. Prod. Repts. 21:1‐49.
   Borchardt, J.K. 1996. A short history of quinine. Drug News Persp. 9:116‐120.
   Boyd, M.R., Farina, C., Belfiore, P., Gagliardi, S., Kim, J.W., Hayakawa, Y., Beutler, J.A., McKee, T.C., Bowman, B.J., and Bowman, E.J. 2001. Discovery of a novel antitumor benzolactone enamide class that selectively inhibits mammalian vacuolar‐type (H+)‐ATPases. J. Pharmacol. Exp. Ther. 297:114‐120.
   Brehm, L., Hjeds, H., and Krogsgaard‐Larsen, P. 1972. The structure of muscimol, a GABA analogue of restricted conformation. Acta Chem. Scand. 26:1298‐1299.
   Buckingham, J. and Thompson, S. 1997. The dictionary of natural products and other information sources for natural products scientists. In Phytochemical Diversity—A Source of New Industrial Products (S. Wrigley, M. Hayes, R. Thomas, and E. Chrystal, eds.) pp. 53‐67. Royal Society of Chemistry, London.
   Bugni, T.S., Harper, M.K., McCulloch, M.W., Reppart, J., and Ireland, C.M. 2008. Fractionated marine invertebrate extract libraries for drug discovery. Molecules 13:1372‐1383.
   Burke, M.D., Berger, E.M., and Schreiber, S.L. 2003. Generating diverse skeletons of small molecules combinatorially. Science 302:613‐618.
   Butler, L.G. 1992. Antinutritional effects of condensed and hydrolyzable tannins. Basic Life Sci. 59:693‐698.
   Butler, M.S. 2008. Natural products to drugs: Natural product‐derived compounds in clinical trials. Nat. Prod. Rep. 25:475‐516.
   Cardellina, J.H. II, Munro, M.H.G., Fuller, R.W., Manfredi, K.P., McKee, T.C., Tischler, M., Bokesch, H.R., Gustafson, K.R., Beutler, J.A., and Boyd, M.R. 1993. A chemical screening strategy for the dereplication and prioritization of HIV‐inhibitory aqueous natural products extracts. J. Nat. Prod. 56:1123‐1129.
   Chain, E., Florey, H.W., Gardner, A.D., Heatley, N.G., Jennings, M.A., Orr‐Ewing, J., and Sanders, A.G. 1940. Penicillin as a chemotherapeutic agent. Lancet 236:226‐228.
   Clapp, R.A. and Crook, C. 2001. Drowning in the magic well: Shaman Pharmaceuticals and the elusive value of traditional knowledge. J. Environ. Dev. 11:79‐102.
   Corley, D.G. and Durley, R.C. 1994. Strategies for database dereplication of natural products. J. Nat. Prod. 57:1484‐1490.
   Cragg, G.M. and Newman, D.J. 2005a. International collaboration in drug discovery and development from natural sources. Pure Appl. Chem. 77:1923‐1942.
   Cragg, G.M. and Newman, D.J. 2005b. Plants as a source of anti‐cancer agents. J. Ethnopharmacol. 100:72‐79.
   Dabydeen, D.A., Burnett, J.C., Bai, R., Verdier‐Pinard, P., Hickford, S.J.H., Pettit, G.R., Blunt, J.W., Munro, M.H.G., Gussio, R., and Hamel, E. 2006. Comparison of the activities of the truncated halichondrin B analog NSC 707389 (E7389) with those of the parent compound and a proposed binding site on tubulin. Mol. Pharmacol. 70:1866‐1875.
   Daly, J.W., Spande, T.F., and Garraffo, H.M. 2005. Alkaloids from amphibian skin: A tabulation of over eight‐hundred compounds. J. Nat. Prod. 68:1556‐1575.
   Davies‐Coleman, M.T., Faulkner, D.J., Dubowchik, G.M., Roth, G.P., Polson, C., and Fairchild, C. 1993. A new EGF‐active polymeric pyridinium alkaloid from the sponge Callyspongia fibrosa. J. Org. Chem. 58:5925‐5930.
   Deocaris, C.C., Widodo, N., Wadhwa, R., and Kaul, S.C. 2008. Merger of ayurveda and tissue culture‐based functional genomics: Inspirations from systems biology. J. Transl. Med. 6:14.
   DiCesare, D., DuPont, H.L., Mathewson, J.J., Ashley, D., Martinez‐Sandoval, F., Pennington, J.E., and Porter, S.B. 2002. A double blind, randomized, placebo‐controlled study of SP‐303 (Provir) in the symptomatic treatment of acute diarrhea among travelers to Jamaica and Mexico. Am. J. Gastroenterol. 97:2585‐2588.
   Dinan, L. and Lafont, R. 2006. Effects and applications of arthropod steroid hormones (ecdysteroids) in mammals. J. Endocrinol. 191:1‐8.
   Donadio, S., Staver, M.J., McAlpine, J.B., Swanson, S.J., and Katz, L. 1991. Modular organization of genes required for complex polyketide biosynthesis. Science 252:675‐679.
   Eldridge, G.R., Vervoort, H.C., Lee, C.M., Cremin, P.A., Williams, C.T., Hart, S.M., Goering, M.G., O'Neil‐Johnson, M., and Zeng, L. 2002. High‐throughput method for the production and analysis of large natural product libraries for drug discovery. Anal. Chem. 74:3963‐3971.
   Ellson, R., Stearns, R., Mutz, M., Brown, C., Browning, B., Harris, D., Qureshi, S., Shieh, J., and Wold, D. 2005. In situ DMSO hydration measurements of HTS compound libraries. Comb. Chem. High Throughput Screen. 8:489‐498.
   Epstein, S. and López‐Garcia, P. 2008. “Missing” protists: A molecular prospective. Biodivers. Conserv. 17:261‐276.
   Evans, D.A., Carter, P.H., Carreira, E.M., Charette, A.B., Prunet, J.A., and Lautens, M. 1999. Total synthesis of bryostatin 2. J. Am. Chem. Soc. 121:7540‐7552.
   Feng, X. and Siegel, M.M. 2007. FTICR‐MS applications for the structure determination of natural products. Anal. Bioanal. Chem. 389:1341‐1363.
   Fischer, H., Machen, T.E., Widdicombe, J.H., Carlson, T.J., King, S.R., Chow, J.W., and Illek, B. 2004. A novel extract SB‐300 from the stem bark latex of Croton lechleri inhibits CFTR‐mediated chloride secretion in human colonic epithelial cells. J. Ethnopharmacol. 93:351‐357.
   Fleming, A. 1929. On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae. Br. J. Exp. Pathol. 10:226‐236.
   Galm, U. and Shen, B. 2007. Natural product drug discovery: The times have never been better. Chem. Biol. 14:1098‐1104.
   Gates, M. and Tschudi, G. 1956. The synthesis of morphine. J. Am. Chem. Soc. 78:1380‐1393.
   Gay, G.M., Inaba, D.S., Sheppard, C.W., Newmeyer, J.A., and Rappolt, R.T. 1975. Cocaine: History, epidemiology, human pharmacology, and treatment. A perspective on a new debut for an old girl. Clin. Toxicol. 8:149‐178.
   Golik, J., Dubay, G., Groenwald, G., Kawaguchi, H., Konishi, M., Krishnan, B., Ohkuma, H., Saitoh, K., and Doyle, T.W. 1987. Esperamicins, a novel class of potent antitumor antibiotics. 3. Structures of esperamicins A1, A2 and A1b. J. Am. Chem. Soc. 109:3462‐3464.
   Gulland, J.M. and Robinson, R. 1923. The morphine group. Part I. A discussion of the constitutional problem. J. Chem. Soc. 980‐998.
   Gullo, V.P. and Hughes, D.E. 2005. Exploiting new approaches for natural product drug discovery in the biotechnology industry. Drug Disc. Today 2:281‐286.
   Hartwell, J.L. 1967. Plants used against cancer. A survey. Lloydia 30:379‐436.
   Hemmilä, I. and Webb, S. 1997. Time‐resolved fluorometry: An overview of the labels and core technologies for drug screening applications. Drug Disc. Today 2:373‐381.
   Hildebrand, M., Waggoner, L.E., Liu, H., Sudek, S., Allen, S., Anderson, C., Sherman, D.H., and Haygood, M. 2004. bryA: an unusual modular polyketide synthase gene from the uncultivated bacterial symbiont of the marine bryozoan Bugula neritina. Chem. Biol. 11:1543‐1552.
   Holodniy, M., Koch, J., Mistal, M., Maimares Schmidt, J., Khandwala, A., Pennington, J.E., and Porter, S.B. 1999. A double‐blind, randomized, placebo‐controlled phase II study to assess the safety and efficacy of orally administered SP‐303 for the symptomatic treatment of diarrhea in patients with AIDS. Am. J. Gastroenterol. 94:3267‐3273.
   Hostettmann, K., Marston, A., and Hostettmann, M. 1998. Preparative Chromatography Techniques. Applications in Natural Products Isolation. Springer, Berlin.
   Hostettmann, K. and Marston, A. 1995. Saponins. Cambridge University Press, Cambridge, U.K.
   Hu, Y., Li, C., Kulkarni, B.A., Strobel, G., Lobkovsky, E., Torczynski, R.M., and Porco, J.A. Jr. 2001. Exploring chemical diversity of epoxyquinoid natural products: Synthesis and biological activity of (‐)‐jesterone and related molecules. Org. Lett. 3:1649‐1652.
   Johnston, G.A.R., Beart, P.M., Curtis, D.R., Game, C.J.A., McCulloch, R.M., and MacLachlan, R.M. 1972. Bicuculline methochloride as a GABA antagonist. Nat. New Biol. 240:219‐220.
   Keskin, O., Bahar, I., Jernigan, R.L., Myers, T.G., Beutler, J.A., Shoemaker, R.H., Sausville, E.A., and Covell, D.G. 2000. Characterization of anticancer agents by their growth‐inhibitory activity and relationships to mechanism of action and structure. Anti‐Cancer Drug Design 15:79‐98.
   Khanbabaee, K. and Ree, T.v. 2001. Tannins: Classification and definition. Nat. Prod. Rep. 18:641‐649.
   Kulkarni, B.A., Roth, G.P., Lobkovsky, E., and Porco, J.A. Jr. 2002. Combinatorial synthesis of natural product‐like molecules using a first‐generation spiroketal scaffold. J. Comb. Chem. 4:56‐72.
   Lang, G., Mayhudin, N.A., Mitova, M.I., Sun, L., van der Sar, S., Blunt, J.W., Cole, A.L., Ellis, G., Laatsch, H., and Munro, M.H. 2008. Evolving trends in the dereplication of natural product extracts: new methodology for rapid, small‐scale investigation of natural product extracts. J. Nat. Prod. 71:1595‐1599.
   Lerchen, H.G. 2002. Milestones in camptothecin research. Drugs Fut. 27:869‐878.
   Lidert, Z., Wing, K., Polonsky, J., Imakura, Y., Masayoshi, O., Tani, S., Lin, Y.M., Kiyokawa, H., and Lee, K.H. 1987. Insect antifeedant and growth inhibitory activity of forty‐six quassinoids on two species of agricultural pests. J. Nat. Prod. 50:442‐448.
   Lipinski, C.A., Lombardo, F., Dominy, B.W., and Feeney, P.J. 1997. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 23:3‐25.
   Lockemann, G. 1951. Friedrich Wilhelm Serturner, the discoverer of morphine. J. Chem. Ed. 28:277‐279.
   McKee, T.C., Covington, C.D., Fuller, R.W., Bokesch, H.R., Young, S., Cardellina, J.H. II, Kadushin, M.R., Soejarto, D.D., Stevens, P.F., Cragg, G.M., and Boyd, M.R. 1998a. Pyranocoumarins from tropical species of the genus Calophyllum: A chemotaxonomic study of extracts in the National Cancer Institute collection. J. Nat. Prod. 61:1252‐1256.
   McKee, T.C., Galinis, D.L., Pannell, L.K., Cardellina, J.H. II, Laakso, J., Ireland, C.M., Murray, L., Capon, R.J., and Boyd, M.R. 1998b. The lobatamides, novel cytotoxic macrolides from southwestern Pacific tunicates. J. Org. Chem. 63:7805‐7810.
   Mendola, D. 2003. Aquaculture of three phyla of marine invertebrates to yield bioactive metabolites: process developments and economics. Biomol. Eng. 20:441‐458.
   Moore, R.E. and Bartolini, G. 1981. Structure of palytoxin. J. Am. Chem. Soc. 103:2491‐2494.
   Moriya, T., Saito, K., Kurita, H., Matsumoto, K., Otake, T., Mori, H., Morimoto, M., Ueba, N., and Kunita, N. 1993. A new candidate for an anti‐HIV‐1 agent: Modified cyclodextrin sulfate (mCDS71). J. Med. Chem. 36:1674‐1677.
   Mothes, K. 1969. Die Alkaloide im Stoffwechsel der Pflanze. Experientia 25:225‐239.
   Mullin, R. 2008. Merck cuts sales jobs and halts natural products research. Chem. Eng. News 86(19):12.
   Munro, M.H., Blunt, J.W., Dumdei, E.J., Hickford, S.J., Lill, R.E., Li, S., Battershill, C.N., and Duckworth, A.R. 1999. The discovery and development of marine compounds with pharmaceutical potential. J. Biotechnol. 70:15‐25.
   Nass, R., Merchant, K.M., and Ryan, T. 2008. Caenorhabditis elegans in Parkinson's disease drug discovery: Addressing an unmet medical need. Mol. Interv. 8:284‐293.
   Newman, D.J. 2008. Natural products as leads to potential drugs: An old process or the new hope for drug discovery? J. Med. Chem. 51:2589‐2599.
   Newman, D.J. and Cragg, G.M. 2004. Marine natural products and related compounds in clinical and advanced preclinical trials. J. Nat. Prod. 67:1216‐1238.
   Newman, D.J. and Cragg, G.M. 2006. Natural products from invertebrates and microbes as modulators of antitumor targets. Curr. Drug Targets 7:279‐304.
   Newman, D.J. and Cragg, G.M. 2007. Natural products as sources of new drugs over the last 25 years. J. Nat. Prod. 70:461‐477.
   Newman, S. 2007. Eribulin, a simplified ketone analog of the tubulin inhibitor halichondrin B, for the potential treatment of cancer. Curr. Opin. Investig. Drugs 8:1057‐1066.
   Nishizuka, Y. 1984. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature 308:693‐698.
   Paul, V.J. and Ritson‐Williams, R. 2008. Marine chemical ecology. Nat. Prod. Rep. 25:662‐695.
   Paull, K.D., Shoemaker, R.H., Hodes, L., Monks, A., Scudiero, D.A., Rubinstein, L., Plowman, J., and Boyd, M.R. 1989. Display and analysis of patterns of differential activity of drugs against human tumor cell lines: Development of mean graph and COMPARE algorithm. J. Natl. Cancer Inst. 81:1088‐1092.
   Paull, K.D., Lin, C.M., Malspeis, L., and Hamel, E. 1992. Identification of novel antimitotic agents acting at the tubulin level by computer‐assisted evaluation of differential cytotoxicity data. Cancer Res. 52:3892‐3900.
   Pettit, G.R., Herald, C.L., Boyd, M.R., Leet, J.E., Dufresne, C., Doubek, D.L., Schmidt, J.M., Cerny, R.L., Hooper, J.N., and Rutzler, K.C. 1991a. Isolation and structure of the cell growth inhibitory constituents from the Pacific marine sponge Axinella sp. J. Med. Chem. 34:3339‐3340.
   Pettit, G.R., Sengupta, D., Herald, C.L., Sharkey, N.A., and Blumberg, P.M. 1991b. Synthetic conversion of bryostatin 2 to bryostatin 1 and related bryopyrans. Can. J. Chem. 69:856‐860.
   Piel, J. 2002. A polyketide synthase‐peptide synthetase gene cluster from an uncultured bacterial symbiont of Paederus beetles. Proc. Natl. Acad. Sci. U.S.A. 99:14002‐14007.
   Rabe, P. 1908. Information on the china alcaloide. VIII. Announcement: The constitution of cinchonines. Ber. Deutsch. Chem. Ges. 41:62‐70.
   Raffauf, R.F. 1996. Plant Alkaloids. A Guide to Their Discovery and Distribution. Food Products Press, Binghamton, N.Y.
   Reynolds, W.F. and Enriquez, R.G. 2002. Choosing the best pulse sequences, acquisition parameters, postacquisition processing strategies, and probes for natural product structure elucidation by NMR spectroscopy. J. Nat. Prod. 65:221‐244.
   Rompler, H., Staubert, C., Thor, D., Schulz, A., Hofreiter, M., and Schoneberg, T. 2007. G protein‐coupled time travel: Evolutionary aspects of GPCR research. Mol. Interv. 7:17‐25.
   Safrin, S., McKinley, G., McKeough, M., Robinson, D., and Spruance, S.L. 1994. Treatment of acyclovir‐unresponsive cutaneous herpes simplex virus infection with topically applied SP‐303. Antiviral Res. 25:185‐192.
   Saporito, R.A., Donnelly, M.A., Hoffman, R.L., Garraffo, H.M., and Daly, J.W. 2003. A siphonotid millipede (Rhinotus) as the source of spiropyrrolizidine oximes of dendrobatid frogs. J. Chem. Ecol. 29:2781‐2786.
   Saporito, R.A., Garraffo, H.M., Donnelly, M.A., Edwards, A.L., Longino, J.T., and Daly, J.W. 2004. Formicine ants: An arthropod source for the pumiliotoxin alkaloids of dendrobatid poison frogs. Proc. Natl. Acad. Sci. U.S.A. 101:8045‐8050.
   Saporito, R.A., Donnelly, M.A., Norton, R.A., Garraffo, H.M., Spande, T.F., and Daly, J.W. 2007. Oribatid mites as a major dietary source for alkaloids in poison frogs. Proc. Natl. Acad. Sci. U.S.A. 104:8885‐8890.
   Schaufelberger, D.E., Koleck, M.P., Beutler, J.A., Vatakis, A.M., Alvarado, A.B., Andrews, P., Marzo, L.V., Muschik, G.M., Roach, J., Ross, J.T., Lebherz, W.B., Reeves, M.P., Eberwein, R.M., Rodgers, L.L., Testerman, R.P., Snader, K.M., and Forenza, S. 1991. The large‐scale isolation of bryostatin 1 from Bugula neritina following current Good Manufacturing Practices. J. Nat. Prod. 54:1265‐1270.
   Schmitz, F.J., Hollenbeak, K.H., and Campbell, D.C. 1978. Marine natural products: Halitoxin, toxic complex of several marine sponges of the genus Haliclona. J. Org. Chem. 43:3916‐3922.
   Schröder, F.C., Farndon, J.R., Attygalle, A.B., Smedley, S.R., Eisner, T., and Meinwald, J. 1998. Combinatorial chemistry in insects: A library of defensive macrocyclic polyamines. Science 281:428‐431.
   Simmons, T.L., Coates, R.C., Clark, B.R., Engene, N., Gonzalez, D., Esquenazi, E., Dorrestein, P.C., and Gerwick, W.H. 2008. Biosynthetic origin of natural products isolated from marine microorganism‐invertebrate assemblages. Proc. Natl. Acad. Sci. U.S.A. 105:4587‐4594.
   Sittenfeld, A., Tamayo, G., Nielsen, V., Jiménez, A., Hurtado, P., Chinchilla, M., Guerrero, O., Mora, M.A., Rojas, M., Blanco, R., Alvarado, E., Gutiérrez, J.M., and Janzen, D.H. 1999. Costa Rican International Cooperative Biodiversity Group: Using insects and other arthropods in biodiversity prospecting. Pharm. Biol. 37:55‐68.
   Spjut, R.W. 2005. Relationships between plant folklore and antitumor activity: An historical review. Sida 21:2205‐2241.
   Sternson, S.M., Wong, J.C., Grozinger, C.M., and Schreiber, S.L. 2001. Synthesis of 7200 small molecules based on a substructural analysis of the histone deacetylase inhibitors trichostatin and trapoxin. Org. Lett. 3:4239‐4242.
   Stevens, C.L., Taylor, K.G., Munk, M.E., Marshall, W.S., Noll, K., Shah, G.D., Shah, L.G., and Uzu, K. 1965. Chemistry and structure of mitomycin C. J. Med. Chem. 8:1‐10.
   Stierle, A., Strobel, G., and Stierle, D. 1993. Taxol and taxol production by Taxomyces andreanae, an endophytic fungus of Pacific yew. Science 260:214‐216.
   Suzumura, K., Takahashi, I., Matsumoto, H., Nagai, K., Setiawan, B., Rantiatmodjo, R.M., Suzuki, K., and Nagano, N. 1997. Structural elucidation of YM‐75518, a novel antifungal antibiotic isolated from Pseudomonas sp. Q38009. Tetrahedron Lett. 38:7573‐7576.
   Tang, P., Mamdani, F., Hu, X., Liu, J.O., and Yu, B. 2007. Synthesis of OSW saponin analogs with modified sugar residues and their antiproliferative activities. Bioorg. Med Chem. Lett. 17:1003‐1007.
   Tang, W. and Eisenbrand, G. 1992. Chinese Drugs of Plant Origin: Chemistry, Pharmacology, and Use in Traditional and Modern Medicine. Springer‐Verlag, Berlin.
   Thoms, C., Ebel, R., and Proksch, P. 2006. Sequestration and possible role of dietary alkaloids in the sponge‐feeding mollusk Tylodina perversa. Prog. Mol. Subcell. Biol. 43:261‐275.
   Tseng, M.H., Chou, C.H., Chen, Y.M., and Kuo, Y.H. 2001. Allelopathic prenylflavanones from the fallen leaves of Macaranga tanarius. J. Nat. Prod. 64:827‐828.
   Uemura, D., Hirata, Y., Iwashita, T., and Naoki, H. 1985a. Studies on palytoxins. Tetrahedron. 41:1007‐1017.
   Uemura, D., Takahashi, K., Yamamoto, T., Katayama, C., Tanaka, J., Okumura, Y., and Hirata, Y. 1985b. Norhalichondrin A: An antitumor polyether macrolide from a marine sponge. J. Am. Chem. Soc. 107:4796‐4798.
   Umezawa, H. 1976. Structure and action of bleomycin. Prog. Biochem. Pharmacol. 11:18‐27.
   Wagenaar, M.M. 2008. Pre‐fractionated microbial samples—The second generation natural products library at Wyeth. Molecules 13:1406‐1426.
   Wall, M.E., Wani, M.C., Brown, D.M., Fullas, F., Olwald, J.B., Josephson, F.F., Thornton, N.M., Pezzuto, J.M., Beecher, C.W.W., Farnsworth, N.R., Cordell, G.A., and Kinghorn, A.D. 1996. Effect of tannins on screening of plant extracts for enzyme inhibitory activity and techniques for their removal. Phytomed. 3:281‐285.
   Wang, Y., Habgood, G.J., Christ, W.J., Kishi, Y., Littlefield, B.A., and Yu, M.J. 2000. Structure‐activity relationships of halichondrin B analogues: Modifications at C.30‐C.38. Bioorg. Med. Chem. Lett. 10:1029‐1032.
   Wani, M.C. and Wall, M.E. 1969. Plant antitumor agents. II. The structure of two new alkaloids from Camptotheca acuminata. J. Org. Chem. 34:1364‐1367.
   Wani, M.C., Taylor, H.L., Wall, M.E., Coggon, P., and 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. 93:2325‐2327.
   Weinstein, J.N., Kohn, K.W., Grever, M.R., Viswanadhan, V.N., Rubinstein, L.V., Monks, A.P., Scudiero, D.A., Welch, L., Koutsoukos, A.D., Chiausa, A.J., and Paull, K.D. 1992. Neural computing in cancer drug development: Predicting mechanism of action. Science 258:447‐451.
   Weinstein, J.N., Myers, T.G., O'Connor, P.M., Friend, S.H., Fornace, A.J., Kohn, K.W., Fojo, T., Bates, S.E., Rubinstein, L.V., Anderson, N.L., Buolamwini, J.K., van Osdol, W.W., Monks, A.P., Scudiero, D.A., Sausville, E.A., Zaharevitz, D.W., Bunow, B., Viswanadhan, V.N., Johnson, G.S., Wittes, R.E., and Paull, K.D. 1997. An information‐intensive approach to the molecular pharmacology of cancer. Science 275:343‐349.
   Wender, P.A., Clarke, M.O., and Horan, J.C. 2005. Role of the A‐ring of bryostatin analogues in PKC binding: synthesis and initial biological evaluation of new A‐ring‐modified bryologs. Org. Lett. 7:1995‐1998.
   Wender, P.A., Dechristopher, B.A., and Schrier, A.J. 2008. Efficient synthetic access to a new family of highly potent bryostatin analogues via a Prins‐driven macrocyclization strategy. J. Am. Chem. Soc. 130:6658‐6659.
   Wenzel, R.P. 2004. The antibiotic pipeline—Challenges, costs, and values. N. Engl. J. Med. 351:523‐526.
   Williams, J.E. 2001. Review of antiviral and immunomodulating properties of plants of the Peruvian rainforest with a particular emphasis on Una de Gato and Sangre de Grado. Altern. Med. Rev. 6:567‐579.
   Willstätter, R. and Müller, W. 1898. Ketones of the tropine group. XII. Constitution of ecgonine. Ber. Deutsch. Chem. Ges. 31:2655‐2669.
   Wosikowski, K., Schuurhuis, D., Johnson, K., Paull, K.D., Myers, T.G., Weinstein, J.N., and Bates, S.E. 1997. Identification of epidermal growth factor receptor and c‐erbB2 pathway inhibitors by correlation with gene expression patterns. J. Natl.Cancer Inst. 89:1505‐1515.
   Wyde, P.R., Ambrose, M.W., Meyerson, L.R., and Gilbert, B.E. 1993. The antiviral activity of SP‐303, a natural polyphenolic polymer, against respiratory syncytial and parainfluenza type 3 viruses in cotton rats. Antiviral Res. 20:145‐154.
   Wynberg, R. 2004. Rhetoric, realism and benefit‐sharing: Use of traditional knowledge of Hoodia species in the development of an appetite suppressant. J. World Intellectual Property 7:851‐876.
   Xu, Z., Metsä‐Ketelä, M., and Hertweck, C. 2009. Ketosynthase III as a gateway to engineering the biosynthesis of antitumoral derivatives. J. Biotechnol. 140:107‐113.
   Yin, X., Zhou, J., Jie, C., Xing, D., and Zhang, Y. 2004. Anticancer activity and mechanism of Scutellaria barbata extract on human lung cancer cell line A549. Life Sci. 75:2233‐2244.
   Zhang, H., Wang, Y., and Pfeifer, B.A. 2008. Bacterial hosts for natural product production. Mol. Pharm. 5:212‐225.
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library