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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, Canada
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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