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©2001-02


       

Publications -EuroCombi-1 Abstracts
Lecture Abstracts - Keynote and Invited Lectures

KLO1 - The Essential Steps Of MCR (Multicomponent Reaction)-Chemistry
Ivar Ugi
Technical University of München, Munchen, Germany

KLO2 - Novel Polymer Reagents And FTICR-MS High Resolution Analysis of Compound Collections
G. Jung, J. Rademann, S. Weik, T. Seyberth, P. Grosche, D. Schmid
University of Tubingen, Tubingen, Germany

KLO3 - High-Speed Experimentation & Simulation: Recent Advances And Case Studies
Ian E. Maxwell
Avantium Technologies BV, Amsterdam, The Netherlands

KLO4 - Organic Synthesis in Solution-Phase and Solid-Phase toward the Library of Natural and Unnatural Products
Takashi Takahashi
Tokyo Institute of Technology, Tokyo, Japan

KLO5 - Directed Evolution as a means to create Enantioselective Enzymes
Manfred T. Reetz
Max Planck Institute for Coal Research, Mulheim/Ruhr, Germany

ILO1 - From Synthones to Bioactive Molecules: Efficient Strategies in Modern Lead Structure Research
Wolfgang Bender
Medicinal Chemistry I, BAYER AG Business Group Pharma Research, Wuppertal, Germany

IL02 - Revolutionising Resin Handling and Analysis in Solid Phase Synthesis
Mark Bradley
University of Southampton, Southampton, United Kingdom

ILO3 - One Sample - One Fraction Purification Of Compound Libraries Without Online Ms Detection
Hans-Jörg Roth
Novartis Pharma AG, Basel, Switzerland

IL04 - Spatial Libraries Of Backbone Cyclic Peptides And Their Utilization For The Discovery Of Peptidoand Proteinomimetic Drug Leads
Chaim Gilon
Hebrew University, Jerusalem, Israel

IL05 - Combinatorial Methods For Polymer Materials Science
Alamgir Karim
National Institute of Standards and Technology, Gaithersburg, MD, USA

IL06 - Results And Commercialisation - Progress In The Practice Of Combinatorial Materials Science
Peter Cohan
Symyx Technologies, Inc., Santa Clara, CA, USA

IL07 - Combinatorial Quantum Chemistry
Paul G. Mezey
University of Saskatchewan, Saskatoon, Canada

ILO8 - Mutation, Recombination And In Vitro Selection Of Rnas And Proteins
Eörs Szathmáry
Collegium Budapest, Budapest, Hungary

IL09 - Dynamic Combinatorial Chemistry
Olof Ramstrom
ISIS-University Louis Pasteur, Strasbourg, France

IL10 - Variation And Selection In Dynamic Combinatorial Libraries
Alexey V. Eliseev
Therascope AG, Heidelberg, Germany

IL11 - Symmetry And Complementarity In The Molecular World
István Hargittai
Budapest University of Technology and Economics, Budapest, Hungary

KLO1 - The Essential Steps Of MCR (Multicomponent Reaction)-Chemistry
Ivar Ugi
Technical University of München, Munchen, Germany

In 1850 began the chemistry of the MultiComponent Reactions (MCRs) , and nine years later the chemistry of the isocyanides was introduced. However, for a whole century these two areas of chemistry were separate. The only exception was the Passerini reaction. The isocyanides were not well available, and their whole chemistry was a rather empty part of organic chemistry.

The isocyanides became generally well available in 1958 , and one year later the Four Component Reaction of the isocyanides (U-4CR) was introduced. In 1961 their libraries were proposed. Although thus a new era of isocyanide chemistry had been started, for many decades only rather few research groups were active in this field.

It was early recognized that it should be possible to prepare derivatives of a-aminoacids and peptides by the stereoselective

U-4CR, but only recently such U-4CRs could sufficiently well be accomplished. Already in 1961 B-lactam derivatives
were prepared by the U-4CR, and since then many B-lactam antibiotics and related compounds were prepared by the
U-4CR. Recently also the one-pot synthesis of the Carbapenam derivatives could be achieved by an U-4CR.

In the last decade of the second millennium the chemistry of the MCRs became unusually active. In 1993 Domling and Ugi introduced a synthesis by a one-pot reaction of seven components, and one year later it was demonstrated that the MCRs of the isocyanides with more than four components correspond to unions of the U-4CR with further reactions. Subsequently Ugi et al. generalized the formation of products by sequences of U-4CRs, MCRs with up to nine components where some educts can obtained.

In 1995 Armstrong introduced the very efficient and successful search after new desirable pharmaceutical products from sequences of MCR libraries by a mathematically oriented program. Recently Weber et al. have introduced a computer program that can assist the search of desirable products from MCR libraries.

KLO2 - Novel Polymer Reagents And FTICR-MS High Resolution Analysis of Compound Collections
G. Jung, J. Rademann, S. Weik, T. Seyberth, P. Grosche, D. Schmid
University of Tubingen, Tubingen, Germany

Solid-supported 1-aryl-3-alkyl triazenes were developed for the alkylating esterification of structurally diverse carboxylic acids including compound libraries bearing a broad range of functionalities such as peptides. The alkylating polymers are capable of releasing reactive carbenium ion intermediates upon mild activation and have been demonstrated as efficient diazoalkane analogues. The various alkyl esters are introduced via numerous and diverse primary amines.

Polymer-supported oxidation of alcohols can be conducted very efficiently by employing oxoammonium salts, the reactive intermediates in Tempo oxidations. These highly reactive salts could be prepared and isolated on the polymeric support, and were used for the conversion of single compounds as well as of complex mixtures of 10 and 20 alcohols.

For the characterization of complex libraries ES-FTJCR-MS is the method of choice due to ultrahigh resolution, very high mass accuracy, high speed and high sensitivity. The potentials of ES-FTICR-MS are exemplified by the analysis of a library of 144 diverse pyrazoles synthesized by A. Furka's split-mix-method.


KLO3 - High-Speed Experimentation & Simulation: Recent Advances And Case Studies
Ian E. Maxwell
Avantium Technologies BV, Amsterdam, The Netherlands


Integrated high-speed experimentation & simulation (HSE&S) technology can be described as a combination of enabling technologies that are deployed to screen, for example, new catalysts and optimal process conditions at high throughput rates by integrating the use of robotic synthesis, reactor miniaturization, parallelism, high-speed analytical techniques combined with informatics, data management and simulation. This approach enables new processes and products to be brought to market at lower cost and dramatically shorter development times. It also increases the chances of technical success and innovation through greater parameter diversity in the screening phase and thus improves the robustness of the final process design.

HSE&S technology is creating a new paradigm in research and development methodologies for many sectors of industry such chemicals, pharmaceuticals and energy processing but also in new materials research and can thus be considered as game-changing technology".

Some concrete examples will be given where HSE&S technologies have indeed resulted in the rapid discovery of new and highly innovative catalyst systems for both pharmaceutical and chemical applications. Further, the scalability of the HSE&S fast screening systems enables these catalysts to be rapidly developed and commercialised.

Some future opportunities and challenges in this exciting new field will also be discussed.


KLO4 - Organic Synthesis in Solution-Phase and Solid-Phase toward the Library of Natural and Unnatural Products
Takashi Takahashi
Tokyo Institute of Technology, Tokyo, Japan

A library synthesis of small molecules is very important not only for drug discovery but also for finding a novel material. Solution-phase and Solid-phase syntheses of. phytoalexin elicitor active oligosaccharides, activated vitamin D3 derivatives and peptide minetics of b-strand secondary structure are presented.


KLO5 - Directed Evolution as a means to create Enantioselective Enzymes
Manfred T. Reetz
Max Planck Institute for Coal Research, Mulheim/Ruhr, Germany

In enantioselective transition metal catalysis, the development of a single highly effective chiral catalyst requires the laborious preparation and testing of a large number of ligands. Alternatively, biocatalysts can be used, but by nature the problem of substrate specificity persists.

A radically different approach to the development of enantioselective catalysts is described, namely directed evolution as a method to stepwise increase the enantioselectivity of a given unselective enzyme. The underlying principle - "evolution in the test tube" - does not require any knowledge of the enzyme structure or of its catalytic mechanism. Proper molecular biological methods for random mutagenesis and expression of genes coupled with an efficient screening system for the rapid identification of enantioselective mutants form the basis of our strategy. The principle is illustrated using a lipase from Pseudomonas aeruginosa, which shows an ee-value of only 2% in the hydrolysis of a chiral ester. An enantioselectivity of> 90% can be obtained by applying the evolutionary method. Sequencing studies reveal the positions at which amino acid substitutions have occurred ("hot spots").


ILO1 - From Synthones to Bioactive Molecules: Efficient Strategies in Modern Lead Structure Research
Wolfgang Bender
Medicinal Chemistry I, BAYER AG Business Group Pharma Research, Wuppertal, Germany

In the Life Science industry the innovations of the last decade such as combinatorial chemistry, high-throughput screening and genomics have radically changed the face of discovery research in pharmaceuticals and agrochemicals. The enormous achievements made in these areas have removed historical bottlenecks with respect to the numbers of compounds synthesized and tested but, inevitably, new ones have emerged.

The Bayer Synthon project was initiated six years ago to address some of these bottlenecks.

The Synthon project is a pro-active approach to the management of synthetic building blocks in pharmaceutical and agrochemical research within Bayer. It aims to integrate all aspects of the discovery process for active substances. Bayer's long history and associated chemical heritage have captured an enormous number of diverse chemicals, often exclusive to Bayer but only poorly accessible within the company, providing a fertile ground for our Synthon project.

The Synthon project was set-up as a company-wide effort connecting our chemical expertise throughout the world.

The project aims to secure the availability of suitable synthetic building blocks for current and future needs and goals. Within Bayer, these goals are the identification of leads and their ultimate development into crop protection agents and drugs. In our industry the way these goals are realized is constantly changing.

IL02 - Revolutionising Resin Handling and Analysis in Solid Phase Synthesis
Mark Bradley
University of Southampton, Southampton, United Kingdom

Solid phase chemistry has captured the imagination of the synthetic community both in a supported and in a scavenger sense. At the present time however the pivotal player in this game is a resin that has been used pretty much unmodified for forty years. In my presentation I will describe:
1.) A systematic investigation looking at the effect of cross-linker on synthesis kinetics and synthetic efficiency.
2.) Detail a new method of examining reaction kinetics at the bead level in a microscopic manner.
3.) Look at a number of new supports for supported synthesis. This will include a revolutionary method of resin handling, that offers all the convenience of teabags or Kan methodology in a much simpler format.
4.) A number of new scavenger resins for solution synthesis.
5.) Describe the use of magnetic resins for solution array format synthesis.


ILO3 - One Sample - One Fraction Purification Of Compound Libraries Without Online Ms Detection
Hans-Jörg Roth
Novartis Pharma AG, Basel, Switzerland

A new method will be presented how to use a preparative HPLC equipped with a single wavelength detector for compound purification of libraries with the one sample/one fraction approach without the need for online MS detection. Per injection only the fraction containing the expected product is collected, even if the crude sample is a complex mixture. The prerequisite for this process is an analytical LC-MS/UV run with a defined amount of compound prior to the purification. From the obtained analytical data optimal conditions for UV triggered purification (wavelength, retention time and threshold) are determined. An inhouse developed software automates data processing and delivers the necessary instrument control files for the purification run.


IL04 - Spatial Libraries Of Backbone Cyclic Peptides And Their Utilization For The Discovery Of Peptidoand Proteinomimetic Drug Leads
Chaim Gilon
Hebrew University, Jerusalem, Israel

The design, synthesis and screening of backbone cyclic spatial libraries (a method called Cycloscan) allow the conversion of peptides and active regions of proteins into highly potent, selective, metabolically stable peptidomimetic drug leads with improved bioavailability. The unique feature of Cycloscan is that all the peptides in the spatial libraries have similar primary sequence and they differ from each other in their conformation. The diversity of the spatial sub-libraries is obtained in hierarchical manner using the following diversity elements: the mode of cyclization, the location of the ring along the peptide chain, the ring size and the ring chemistry. Recent examples of the application of Cycloscan to peptides and proteins are (i) a novel long-acting backbone cyclic somatostatin analog with endocrine selectivity that suppress in-vivo growth hormone release but not insulin or glucagon (ii) a backbone cyclic proteinomimetic of the ARM region in the HIV- 1 Tat that inhibit both binding to the viral RNA and nuclear import.


IL05 - Combinatorial Methods For Polymer Materials Science
Alamgir Karim
National Institute of Standards and Technology, Gaithersburg, MD, USA

The use of combinatorial methods -- which comprise a special set of tools and techniques -- enables scientists to rapidly explore a wide range of material characteristics in parallel and on a miniaturized scale. The Combinatorial Methods Program at NIST was initiated to develop this methodology to learn more about materials and their structure, properties and processing, data that can help manufacturers accelerate the development of new materials. The Polymers Division is developing this methodology to learn more about polymeric materials and their structure, properties and processing-- data that can help manufacturers accelerate the development of new materials for the polymer industry. Elegant methods for combinatorial library preparation of polymer coatings have been developed with variations of diverse parameters such as composition, thickness, processing temperature, surface texture and patterning. Vast amounts of data are generated in a few hours that help to understand how these variables affect the material properties, such as coatings wettability or blend phase miscibility. Additional focus areas for both organic and inorganic materials include multiphase materials, electronic materials, biomaterials assay, and materials structure and properties characterization. State of the art on-line data analysis tools, process control methodology and data archival methods are being developed as part of the program.

 

IL06 - Results And Commercialisation - Progress In The Practice Of Combinatorial Materials Science
Peter Cohan
Symyx Technologies, Inc., Santa Clara, CA, USA

Application of high-throughput design, parallel synthesis, high-throughput screening and data analysis is now being practiced across a range of materials science applications, including catalysts, polymers, and electronic materials. A number of organizations have invested in developing programs in specific fields and some programs have yielded results that are moving towards commercialization. What are the success factors necessary to achieve sustainable high throughput workflows that deliver the desired results?

We will discuss the key factors learned in the implementation of successful high throughput programs at Symyx and other firms. These success factors span the technical, including overall workflow, design, synthesis, sample preparation, properties screening, instrument and software integration, databasing, data management, and data mining functions, as well as economic and cultural components.


IL07 - Combinatorial Quantum Chemistry
Paul G. Mezey
University of Saskatchewan, Saskatoon, Canad
a
In complete analogy with synthetic combinatorial chemistry, computational quantum chemistry can also utilize a combinatorial principle of building large libraries of computer databanks of high quality (ab initio quantum chemistry quality) models of medium-size and large molecules, including proteins and other biopolymers. Originally motivated by molecular shape analysis, based on the shapes of fuzzy electron density clouds and the mathematical techniques of topology, the density matrix method (ADMA) of fuzzy electron density fragmentation and the construction of fuzzy molecular fragment electron density clouds have paved the way for a full implementation of combinatorial quantum chemistry. The basis of the combinatorial quantum chemistry method, the constraints represented by the holographic principle of electron densities (any small part of the molecular electron density cloud contains the complete information about all properties of the molecule), the connections with actual, synthetic combinatorial chemistry, and some surprising consequences will be discussed.



ILO8 - Mutation, Recombination And In Vitro Selection Of Rnas And Proteins
Eörs Szathmáry
Collegium Budapest, Budapest, Hungary

Sequence space is a highly multidimensional, discrete space, where all the possible macromolecules of a given type, up to a certain size are accommodated, according to their Hamming distance. It is an exciting question how this sequence space maps onto function space. In the case of RNA molecules we have an increasingly clear picture about this relationship, due to the recent advance in theoretical and experimental studies. The state-of-the-art will be illustrated by the example of catalytic RNA molecules (ribozymes). The size of the genetic alphabet (how many base types build nucleic acids) turns out to be related to the genetic and catalytic capabilities of RNA molecules. The relevance of dynamic combinatorial libraries in the origin of life will also be discussed.


IL09 - Dynamic Combinatorial Chemistry
Olof Ramstrom
ISIS-University Louis Pasteur, Strasbourg, France

Dynamic combinatorial chemistry (DCC) is a new supramolecular concept that extends beyond static combinatorial chemistry towards adaptive/evolutive chemical systems. This concept relies on reversible reactions or interactions between sets of basic components to generate continually interchanging adducts, giving access to dynamic combinatorial libraries (DCLs) whose constituents are all possible combinations of the components available. Such libraries allow for the target-driven generation or amplification of the active constituent(s) of the libraries, thus performing a self-screening process by which the active species are preferentially expressed and retrieved from the DCL. In this study, the implementation of such libraries on biological interactions was examined and dynamic libraries, generated from small arrays of initial precursors, were probed against binding to biological receptors.


IL10 - Variation And Selection In Dynamic Combinatorial Libraries
Alexey V. Eliseev
Therascope AG, Heidelberg, Germany
The major effort of today's combinatorial chemistry is focused on the synthesis and screening of libraries of individual compounds. The alternative approach, use of mixtures (pools) of compounds, is significantly less labor-and resource consuming, but requires elaborate analytical tools to identify effective components in complex mixtures.
This lecture will consider dynamic combinatorial chemistry, an approach to molecular diversity generation and screening that involves a reorganization of pools of compounds, existing in a dynamic equilibrium, via their interactions with the target compound. Such reorganization results in the formation of amplified amounts of those components that form the strongest complexes with the target and thereby simplifies their isolation and identification.

The emphasis in the presentation will be made on two topics: (i) tools that allow one to separate the selection and variation processes in dynamic libraries, which becomes particularly important when dealing with biological targets; (ii) expanding the chemistry of dynamic libraries to combine two or more types of equilibrium processes in dynamic mixtures. Some examples

viii be considered that reflect studies performed by our group in Buffalo and include the following:
.) the synthesis-screening of a mixture of isomers that led to the formation of arginine binders in an evolutionary mode
.) use of oxime ethers as versatile components of dynamic libraries
.) double-level dynamic libraries based on the combination of two reversible reactions, ligand exchange in transition metal :omplexes and imine exchange.

We will present the most recent results on discovery of new RNA ligands in the latter libraries via direct screening by mass pectrometry.

Finally, we will introduce a new start-up company, Therascope AG located in Heidelberg, whose activity focuses on the harmaceutical applications of dynamic combinatorial chemistry.


IL11 - Symmetry And Complementarity In The Molecular World
István Hargittai
Budapest University of Technology and Economics, Budapest, Hungary

With the appearance of combinatorial chemistry, we have lost count of the number of new substances produced in the laboratory. However, this does not mean that we are losing sight of the structure of matter. There are patterns in the structures, Appearing as symmetry. The search for pattern is the most characteristic scientific approach in uncovering the secrets of nature. While symmetry symbolizes pattern, it does not mean that the structures occurring in nature will be always of the highest symmetry possible. As in everything else, there is economy in nature even as regards symmetry.

As early as in 1940, Linus Pauling and Max DelbrUck took up the question of intermolecular forces operative in biological processes. Their considerations were in response to Pascal Jordan's suggestion that a quantum mechanical stabilizing interaction operates preferentially between identical or nearly identical molecules or parts of molecules. Pauling and DelbrUck. suggested precedence for interaction between complementary parts. They argued that the intermolecular interactions give stability to a system of two molecules with complementary structures in juxtaposition rather than two molecules with identical. Structures. Complementariness remained in Pauling's mind when he later discussed molecular replication.

Various symmetry considerations entered the quest for what is known today as the a-helix. Pattern recognition and modeling nvolved information on small molecular structures and resonance theory, and the notion that the most general operation elating an asymmetric object (an amino acid) to another copy (another amino acid) is a rotation-translation equivalent to a helix when repeated. Thus helical symmetry entered the description of biological systems. The revolutionary double helix structure of DNA had further important novel features in which symmetry and complementarily appear in unison. These features are strongly linked to the function of the DNA molecule.

The presentation will make a tour throughout chemistry, with emphasis on biological systems in which appearances of various degrees of symmetry from perfection to asymmetry will figure. Complementarily will be shown to be a twin concept being on par with symmetry, both in utility and even aesthetic appeal.

 

 

 

     
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