Synthesis of Agrochemicals and Agricultural Biotechnology Entering

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Chapter 1

Synthesis of Agrochemicals and Agricultural Biotechnology Entering the 21st Century DavidA.Hunt, DonR.Baker, JosephG.Fenyes, and GregoryS.Basarab

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Cyanamid Agricultural Research Center, American Cyanamid Company, P.O. Box 400, Princeton, NJ 08543-0400 2

Zeneca Agricultural Products, 1200 South 47th Street, Richmond, CA 94804 3

Buckman Laboratories International, Inc., 1256 North McLean Boulevard, Memphis, TN 38108 4

Stine-Haskell Research Center, DuPont Agricultural Products, Newark, DE 19714

The last few years have been witness to dramatic changes in the agrochemical synthesis field. Since many of the approaches of the agrochemical sector to finding new active agents are similar to those in the pharmaceutical field, the newer technologies developed for pharmaceutical research have been embraced by agrochemical research. Among these are combinatorial chemistry and robotics synthesis as well as aggressive acquisition of large compound librariesfromacademic and commercial sources. This delivers greater inputs into the screening process. Robotics are also increasingly being employed for the screening process itself. The prime goal is to satisfy the ever increasing need for new leads compounds. The better new leads thus generated are then optimized by more conventional means or else by means of automated synthesis of more directed compound libraries. Consequently, the potential for agrochemical scientists to continue to provide safer, lower use-rate, more environmentally benign crop protection agents remains high. Concurrently during the past decade, great strides have been made in the adaptation and integration of biotechnology to agricultural production. Much of the work in this area has focused in developing new biological methods of pest control, crops with engineered resistance to pests and herbicides, and products with higher nutritional content. Overall this new technology promises to reduce the environmental load of chemical pesticides. While the development of molecular biology and its subsequent application to agriculture has been no less than spectacular, it has raised many questions concerning the landscape of pest control methodology in the future of global agriculture, particularly with regard to the place of traditional synthesis chemistry. © 1998American Chemical Society

Baker et al.; Synthesis and Chemistry of Agrochemicals V ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

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2 As we approach the dawn of the 21* century there is an ever increasing need for agricultural food and fiber. The world population continues to increase creating progressively more production pressure on dwindling arable land resources (/). Many fear that as we proceed several decades into the 21 century that the world population will become so large that it can no longer feed itself and that the environment will concurrently be destroyed. Many foresee a growth in agrochemical technology to ensure that such catastrophes can be avoided. However, environmental and health fears associated with agrochemicals has greatly increased the regulatory pressure on their use. This has greatly increased the costs of registration and re-registration of agrochemicals. Research and development costs for new agrochemicals have risen to the point that only major markets can justify the great development time and expense for new products. Minor crops find fewer and fewer materials registered for their use, much to the misfortune of those farmers who are effected. Likewise, resistance to single mode of action agrochemicals continues to grow and be a major problem. Resistance is now a common problem in most of the agrochemical markets. It has become such a problem that major efforts are being made to screen large numbers of compounds looking for new lead materials which have novel modes of action compared to current products in order to provide effective control of resistant and non-resistant pest populations. The net result is that agrochemical technology can be expected to partner with biotechnology to solve the problems identified and support the market demands of the world's farmers and indirectly, the world's population. The basic understanding of biological systems on the molecular level coupled with the power of synthesis chemistry has created opportunities which were unimaginable just a decade ago. Molecular biology has enabled researchers to know specific enzyme and receptor targets for small molecular inhibition and characterize the genes that encode them before the compounds movefromresearch to development. This allows refinement of the agrochemical design process either to increase compound potency or decrease the binding to off-target proteins. The power of combinatorial chemistry to provide orders of magnitude greater numbers of compounds for lead identification and the concomitant growth in the development of molecular-based high throughput screens have rapidly altered the research environment during the past few years. In the case of combinatorial chemistry, the pharmaceutical industry first embraced the technology resulting in the birth of companies focusing on the generation and sale of compound libraries. However, agricultural applications of this burgeoning technology are now being explored and exploited. The many and varied ways of discovery of new agrochemicals have been exemplified in this series of ACS Books (2-5). The important discovery of the imidazolinone herbicides by Dr. Marinus Los and his American Cyanamid Co. coworkers is exemplified in the first section. The following three sections demonstrate discoveries in the control of weeds and plant growth; the control of insects, acarids and nematodes; and the control of fungi. Throughout the chapters of this book, the relationship between agrochemical discoveries and their biochemical target-sites of action get particular attention. As our ability to manipulate genes and their protein products improve, the importance of agricultural biotechnology and its partnership with chemistry can be expected to be amplified.

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Baker et al.; Synthesis and Chemistry of Agrochemicals V ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

3 Agricultural Biotechnology In the preface of a 1987 ACS monograph entitled "Biotechnology in Agricultural Chemistry" the authors state "...The only place biotechnology can be sold as a science is on the stock market. Everywhere else, biotechnology is merely a means of developing tools or products that must be applied in some practical way. Biotechnology must compete with the performance, ease of use, effectiveness, and economy of all other methods for doing the same job. It must face the traditions and biases of the user (6). Those criteria today have been met with success in many cases. Biotechnology appears to be ushering science into a new era, with agricultural applications having seemingly boundless potential to enhance productivity, the environment, food safety, and nutritional quality. Some of the most significant developments over the pastfiveyears have resided in the field of transgenic plants which express foreign genes thereby conferring biologically beneficial traits to major crops, ranging from longer shelf life to pest resistance. Transgenic plant technology directed toward herbicide tolerance and insect control attained full approval for agronomic use in key crops in North America in 1995 and 1996. US farmer acceptance of this new tool indicates that this technology in a variety of forms will continue to be a significant force in the future of global crop protection. However, global acceptance is still very much controversial. In a recent article in the Chronicle of Higher Education (7), Nina Fedoroffof the Life Sciences Consortium and Biotechnology Institute at Pennsylvania State University eloquently expresses concern over the need to develop methods to increase agricultural productivity in the face of a rapidly expanding global population. With the current population growth rate, people are consuming more than they are producing. A strong proponent of biotechnology, Ms. Fedoroff indicates in her article that concomitant development and utilization of a variety of technologies will be required in order to meet the increasing needs of the human community. As agrochemicals were lauded as the ultimate in pest control methods decades ago, so too has biotechnology today in some circles. With all of this promise, could there possibly be a down side to biotechnology? Uncertainties have been raised regarding questions of both long- and short-term impacts on health matters, food safety, the environment, and costs relating to both social and economic issues. For example, researchers have long known that transgenic plants can form hybrids with wild relatives. Scientists in Denmark have recently shown that these hybrids can transmit genetic traits to subsequent generations under field conditions (8). Besides speculations of the rapid development of resistance, harmful traits may be transferred between transgenic crops. The incorporation of new genetic material into a host organism gives rise to the production of non-native proteins, which has led to health-related concerns. This type of phenomenon was observed recently when a Brazil nut gene was engineered into soybeans in order to provide enhanced levels of methionine for animal feed. The project was terminated when tests revealed that extractsfromthe genetically altered soybeans caused allergic reactions (9,70). Based on these factors, does synthesis chemistry still have contributions for crop protection, or has it been made obsolete by the development and commercialization of biotechnologically engineered products? Even with all of this unrealized potential, it appears that biotechnology is not the panacea it was once touted to be in the late 1970's.

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Baker et al.; Synthesis and Chemistry of Agrochemicals V ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

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4 Likewise, it is clear that the regulatory landscape for crop protection chemicals has been drastically and irreversibly altered over the past decade. The ability to feed a rapidly growing global population, the increased awareness of the impact that pesticides have on the environment, and the need to minimize cost are clearly the major driving forces for the development of new technologies for agriculture in the 21st century. While synthesis chemistry has established itself as a key factor in conventional farming and biocontrol methods have gained acceptance, synthetic chemicals and genetically engineered biopesticides are not independently the solution for global pest control and enhanced agricultural productivity. Most likely both will be necessary in the farmer's arsenal based on their ability to provide economic value. New products derived from both chemical synthesis and biotechnology with unique modes of action will be required due to the dynamic nature of agriculture. It is most likely that pest management will come to rely on an integration of technologies, combining current methods and technologies with new ones. This approach accurately reflects the state of life sciences research today - the convergence of a variety of scientific disciplines to discover novel applications for both the agricultural and pharmaceutical industries. This evolution of science as applied to agriculture is evident in that many agricultural chemical companies and universities are incorporating new toolsfromboth molecular biology and chemistry into product discovery efforts. The following are typical of the great variety of these efforts: 1. The development of plant systems capable of being chemically induced to provide multi-target defenses against pathogens - a process similar in nature to animal cellular immunity. 2. On going attempts to discover natural crop protection agentsfromnatural products. 3. The development of genetically-mediated syntheses of natural products. 4. Development of genes responsible for small molecule synthesis which can be stacked and shuffled, thereby producing novel complex structures. 5. Use of anti sense technology to identify potential herbicide targets. 6. The use of antibody technology as a method to develop surrogate receptors in compound screening. 7. Microbial applications of biotechnology for agricultural uses provide natural products as both commercial entities and templates for analog synthesis, as well as systems for the degradation of waste pesticides and other environmentally hazardous materials. What is the future for synthesis chemistry in light of the rapid development of biotechnology? The advances in the life sciences hinge on increased knowledge in organic chemistry and, by definition, molecular biology has its roots in organic chemistry. Still, "...the science is best described as being between infancy and childhood" {11). With the rapid development of molecular biology, the formal boundaries between these disciplines have become vague. Synthesis chemistry will continue to play an important role in crop protection methods in the future and will continue to evolve to meet challenges presented to molecular biology in support of future developments in biotechnology.

Baker et al.; Synthesis and Chemistry of Agrochemicals V ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

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Literature Cited 1. Klassen, W.; in Eighth International Congress ofPesticide Chemistry, Options 2000; Ragsdale, N.N.; Kearney, P.C.;Plimmer, J. R., Eds; ACS Conference Proceedings Series, Washington, DC, 1995; pp 1-32. 2. Baker, D. R.; Fenyes, J. G.; Basarab, G. S.; Eds., Synthesis and Chemistry of Agrochemicals IV, ACS Symposium Series, 584, Washington, DC, 1995. 3. Baker, D. R.; Fenyes, J. G.; Steffens, J. J.; Eds., Synthesis and Chemistry of Agrochemicals III, ACS Symposium Series, 504, Washington, DC, 1991. 4. Baker, D. R.; Fenyes, J.G.;Moberg W. K.; Eds., Synthesis and Chemistry of Agrochemicals II, ACS Symposium Series, 443, Washington, DC, 1989. 5. Baker, D. R.; Fenyes, J. G.; Moberg W. K.; Cross B.; Eds., Synthesis and Chemistry ofAgrochemicals, ACS Symposium Series, 355, Washington, DC, 1987. 6. LeBaron, H. M.; Mumma, R. O.; Honeycutt, R. C.; Duesing, J. H. in Biotechnology in AgriculturalChemistry;LeBaron, H. M.; Mumma, R. O.; Honeycutt, R. C.; Duesing, J. H., Eds.; ACS Symposium Series 334; American Chemical Society: Washington, DC, 1987;pxi. 7. V. Fedoroff, "Food for a Hungry World: We Must Find Ways to Increase Agricultural Productivity", The Chronicle ofHigher Education 1997, 43, Number 41, pp B4-B5. 8. Mikkelsen, T. R.; Andersen, B.; Joergensen, R. B. Nature 1996, 380 (6569),p31. 9. Beardsley, T. "Advantage: Nature. Could Escaped GenesfromBioengineered Crops Give Weeds a Critical Boost?", Scientific American; May, 1996, p 33. 10. Nordlee, J. Α.; Taylor, S. L.; Townsend, J. Α.; Thomas, L. Α.; Bush, R. K.TheNew England Journal ofMedicine, 1996, 334, pp 688-692. 11. Trost, B.M. "Sculpting Horizons in Organic Chemistry," Science 1985, 227, p 908.

Baker et al.; Synthesis and Chemistry of Agrochemicals V ACS Symposium Series; American Chemical Society: Washington, DC, 1998.