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An analogy between combinatorial chemistry and Monte Carlo computer simulation is pursued. Examples of how to design libraries for both materials discovery and protein molecular evolution are given. For materials discovery, the concept of library redesign, or the use previous experiments to guide the design of new experiments, is introduced. For molecular evolution, examples of how to use ``biased'' Monte Carlo to search the protein sequence space are given. Chemical information, whether intuition, theoretical calculations, or database statistics, can be naturally incorporated as an a priori bias in the Monte Carlo approach to library design in combinatorial chemistry. In this sense, combinatorial chemistry can be viewed as an extension of traditional chemical synthesis.

Creating new chemicals is a complicated process that requires the skills of trained organic chemists. A new methods of synthesizing compounds is revolutionizing organic chemistry. On this program, Dr. Oleg Kolosov discussed the emerging field of combinatorial chemistry.

Creating new chemicals is a complicated process that requires the skills of trained organic chemists. A new methods of synthesizing compounds is revolutionizing organic chemistry. On this program, Dr. Oleg Kolosov discussed the emerging field of combinatorial chemistry.

Creating new chemicals is a complicated process that requires the skills of trained organic chemists. A new methods of synthesizing compounds is revolutionizing organic chemistry. On this program, Dr. Oleg Kolosov discussed the emerging field of combinatorial chemistry.

Creating new chemicals is a complicated process that requires the skills of trained organic chemists. A new methods of synthesizing compounds is revolutionizing organic chemistry. On this program, Dr. Oleg Kolosov discussed the emerging field of combinatorial chemistry.

Creating new chemicals is a complicated process that requires the skills of trained organic chemists. A new methods of synthesizing compounds is revolutionizing organic chemistry. On this program, Dr. Oleg Kolosov discussed the emerging field of combinatorial chemistry.

Creating new chemicals is a complicated process that requires the skills of trained organic chemists. A new methods of synthesizing compounds is revolutionizing organic chemistry. On this program, Dr. Oleg Kolosov discussed the emerging field of combinatorial chemistry.

Creating new chemicals is a complicated process that requires the skills of trained organic chemists. A new methods of synthesizing compounds is revolutionizing organic chemistry. On this program, Dr. Oleg Kolosov discussed the emerging field of combinatorial chemistry.

Creating new chemicals is a complicated process that requires the skills of trained organic chemists. A new methods of synthesizing compounds is revolutionizing organic chemistry. On this program, Dr. Oleg Kolosov discussed the emerging field of combinatorial chemistry.

Creating new chemicals is a complicated process that requires the skills of trained organic chemists. A new methods of synthesizing compounds is revolutionizing organic chemistry. On this program, Dr. Oleg Kolosov discussed the emerging field of combinatorial chemistry.

Creating new chemicals is a complicated process that requires the skills of trained organic chemists. A new methods of synthesizing compounds is revolutionizing organic chemistry. On this program, Dr. Oleg Kolosov discussed the emerging field of combinatorial chemistry.

Creating new chemicals is a complicated process that requires the skills of trained organic chemists. A new methods of synthesizing compounds is revolutionizing organic chemistry. On this program, Dr. Oleg Kolosov discussed the emerging field of combinatorial chemistry.

Our overall goal of this US Army Breast Cancer Grant entitled "Novel Combinatorial Chemistry-Derived Inhibitors of Oncogenic Phosphatases" is to identify and develop novel therapeutic agents for human breast cancer. During the past year we synthesized a novel second generation, small molecule library designed on our previous natural product pharmacophore that was targeted against oncogenes implicated in human breast cancer, namely the dual specificity phosphatases (DSP) Cdc25. The new library maintains unique, rigid backbone structures that should provide more structural information about the active site of DSP. Several of the new compounds are potent competitive inhibitors of Cdc25. In addition we have identified the first selective VHR inhibitor, namely FY2-alpha009. This compound should facilitate our studies of the biological function of VHR, which are currently unknown. We continued our studies of the prototype member of the first combinatorial library with the best antiCdc25 activity, namely SC-alpha alpha delta89. We have determined that SC-alpha alpha 89 is selectively cytotoxic to cells, which overexpress Cdc25B due to transformation with SV-40 large T antigen. We have also discovered that SC-alpha alpha 89 disrupts a key mitogenic and antiapoptotic pathway, insulin-like growth factor-1 (lGF-1), and downregulates Cdc2 expression. SC--alpha alpha89 also blocks human breast cancer (MDA-MB-231) and other cells at G2IM consistent with Cdc25B or C inhibition. Thus, our combinatorial approach for selective DSP inhibitors remains very promising.

Our overall goal of this US Army Breast Cancer Grant entitled "Novel Combinatorial Chemistry-Derived Inhibitors of Oncogenic Phosphatases" is to identify and develop novel therapeutic agents for human breast cancer. During the past year we synthesized a novel second generation, small molecule library designed on our previous natural product pharmacophore that was targeted against oncogenes implicated in human breast cancer, namely the dual specificity phosphatases (DSP) Cdc25. The new library maintains unique, rigid backbone structures that should provide more structural information about the active site of DSP. Several of the new compounds are potent competitive inhibitors of Cdc25. In addition we have identified the first selective VHR inhibitor, namely FY2-alpha009. This compound should facilitate our studies of the biological function of VHR, which are currently unknown. We continued our studies of the prototype member of the first combinatorial library with the best antiCdc25 activity, namely SC-alpha alpha delta89. We have determined that SC-alpha alpha 89 is selectively cytotoxic to cells, which overexpress Cdc25B due to transformation with SV-40 large T antigen. We have also discovered that SC-alpha alpha 89 disrupts a key mitogenic and antiapoptotic pathway, insulin-like growth factor-1 (lGF-1), and downregulates Cdc2 expression. SC--alpha alpha89 also blocks human breast cancer (MDA-MB-231) and other cells at G2IM consistent with Cdc25B or C inhibition. Thus, our combinatorial approach for selective DSP inhibitors remains very promising.

The purpose of this paper is to speculate, or suggest, how combinatorial chemistry may influence the environment and environmental policy. Technological change is frequently identified as a primary determinant of how human activities affect the environment and human health. Yet policy makers often have little opportunity to posit how technology development may change or affect current policies in the future. This paper is an attempt to look at one technology, combinatorial chemistry, and to suggest how it may or may not affect our current system. The genesis for this paper was a talk given by Dr. Paul Anderson, Vice President of Chemical and Physical Sciences, DuPont-Merck at a RAND Critical Technologies Seminar (The Critical Technologies Institute at RAND has since been renamed the Science and Technology Policy Institute). In his presentation he suggested that combinatorial chemistry would enable the simultaneous synthesis of significantly greater numbers of compounds than are routinely synthesized today.

The purpose of this paper is to speculate, or suggest, how combinatorial chemistry may influence the environment and environmental policy. Technological change is frequently identified as a primary determinant of how human activities affect the environment and human health. Yet policy makers often have little opportunity to posit how technology development may change or affect current policies in the future. This paper is an attempt to look at one technology, combinatorial chemistry, and to suggest how it may or may not affect our current system. The genesis for this paper was a talk given by Dr. Paul Anderson, Vice President of Chemical and Physical Sciences, DuPont-Merck at a RAND Critical Technologies Seminar (The Critical Technologies Institute at RAND has since been renamed the Science and Technology Policy Institute). In his presentation he suggested that combinatorial chemistry would enable the simultaneous synthesis of significantly greater numbers of compounds than are routinely synthesized today.

The purpose of this paper is to speculate, or suggest, how combinatorial chemistry may influence the environment and environmental policy. Technological change is frequently identified as a primary determinant of how human activities affect the environment and human health. Yet policy makers often have little opportunity to posit how technology development may change or affect current policies in the future. This paper is an attempt to look at one technology, combinatorial chemistry, and to suggest how it may or may not affect our current system. The genesis for this paper was a talk given by Dr. Paul Anderson, Vice President of Chemical and Physical Sciences, DuPont-Merck at a RAND Critical Technologies Seminar (The Critical Technologies Institute at RAND has since been renamed the Science and Technology Policy Institute). In his presentation he suggested that combinatorial chemistry would enable the simultaneous synthesis of significantly greater numbers of compounds than are routinely synthesized today.

The purpose of this paper is to speculate, or suggest, how combinatorial chemistry may influence the environment and environmental policy. Technological change is frequently identified as a primary determinant of how human activities affect the environment and human health. Yet policy makers often have little opportunity to posit how technology development may change or affect current policies in the future. This paper is an attempt to look at one technology, combinatorial chemistry, and to suggest how it may or may not affect our current system. The genesis for this paper was a talk given by Dr. Paul Anderson, Vice President of Chemical and Physical Sciences, DuPont-Merck at a RAND Critical Technologies Seminar (The Critical Technologies Institute at RAND has since been renamed the Science and Technology Policy Institute). In his presentation he suggested that combinatorial chemistry would enable the simultaneous synthesis of significantly greater numbers of compounds than are routinely synthesized today.

We have initiated our search for anion receptors using the hypothesis that the binding of complex anions (e.g. ATP, ADP, nitrotyrosine, phosphotyrosine, etc for these model studies), will require a domain for the binding of the more hydrophobic portion of the molecule (the nucleobase) and a domain for desolvating and subsequently binding the phosphate portion of the anion. To achieve this end we have designed monomers that will form a cavity to bind the organic portion of the organophosphates selectively while also providing electrostatic interactions to stabilize the phosphate anion. Disulfide exchange was selected as the reversible reaction to generate the library, as it is compatible with aqueous solution and is well established for DCC. In addition, we have developed thioester exchange as an alternative reversible reaction because it is significantly faster than disulfide exchange.

Strategies for searching the space of variables in combinatorial chemistry experiments are presented, and a random energy model of combinatorial chemistry experiments is introduced. The search strategies, derived by analogy with the computer modeling technique of Monte Carlo, effectively search the variable space even in combinatorial chemistry experiments of modest size. Efficient implementations of the library design and redesign strategies are feasible with current experimental capabilities.

Strategies for searching the space of variables in combinatorial chemistry experiments are presented, and a random energy model of combinatorial chemistry experiments is introduced. The search strategies, derived by analogy with the computer modeling technique of Monte Carlo, effectively search the variable space even in combinatorial chemistry experiments of modest size. Efficient implementations of the library design and redesign strategies are feasible with current experimental capabilities.

Strategies for searching the space of variables in combinatorial chemistry experiments are presented, and a random energy model of combinatorial chemistry experiments is introduced. The search strategies, derived by analogy with the computer modeling technique of Monte Carlo, effectively search the variable space even in combinatorial chemistry experiments of modest size. Efficient implementations of the library design and redesign strategies are feasible with current experimental capabilities.

The overall goal of this US Army Breast Cancer Grant entitled Novel Combinatorial Chemistry-Derived Inhibitors of Oncogenic Phosphatases was to develop novel methods to synthesize by combinatorial methods libraries of small molecules and to test small molecules for their ability to inhibit protein phosphatases thought to be important for the development of breast cancer. During the past three years we have synthesized more than 1,000 novel small molecules designed on natural products. These pharmacophores were used to build libraries by combinatorial methods. We tested more than 11,000 existing or new compounds for their ability to inhibit Cdc25 in vitro. Several of the new compounds are potent partial competitive inhibitors of Cdc25. We have established that these compounds also inhibit Cdc25 within cells and have the ability to inhibit the growth of human breast cancer MCF-7 and MDA-MB-231 cells. The selectivity of these inhibitors against other protein phosphatases has been established and one of the compounds has been tested in vivo and been shown to have antitumor activity. These results suggest that our approach to the design and identification of novel therapeutics agents directed against human breast cancer is promising.

Catalyzed based olefin metathesis is a very valuable and useful tool in synthetic organic chemistry. Our research goals consisted of employing olefin metathesis in the synthesis of peptidomimetics, and studying the feasibility of this method in dynamic combinatorial chemistry and molecular imprinting of nerve agents. One of the approaches to the development of peptidomimetics is to attach biologically significant functional groups, such as amino acid side chains, to a scaffold. Grubbs' second generation ruthenium catalyst was used to couple phenylalanine to a 17- membered lactam using cross-metathesis in 48% yield with an E:Z ratio of 1.2:1. The CM product of two phenylalanine amino acids was isolated in 45% yield and found to be predominantly trans. A series of synthetic steps were needed to construct the 17- membered lactam, including the fundamental RCM reaction. The reversibility of the cross metathesis of this macro cyclic system was demonstrated, which is essential to the development of a dynamic combinatorial library.

Catalyzed based olefin metathesis is a very valuable and useful tool in synthetic organic chemistry. Our research goals consisted of employing olefin metathesis in the synthesis of peptidomimetics, and studying the feasibility of this method in dynamic combinatorial chemistry and molecular imprinting of nerve agents. One of the approaches to the development of peptidomimetics is to attach biologically significant functional groups, such as amino acid side chains, to a scaffold. Grubbs' second generation ruthenium catalyst was used to couple phenylalanine to a 17- membered lactam using cross-metathesis in 48% yield with an E:Z ratio of 1.2:1. The CM product of two phenylalanine amino acids was isolated in 45% yield and found to be predominantly trans. A series of synthetic steps were needed to construct the 17- membered lactam, including the fundamental RCM reaction. The reversibility of the cross metathesis of this macro cyclic system was demonstrated, which is essential to the development of a dynamic combinatorial library.