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Combinatorial
Chemistry & High Throughput Screening
ISSN: 1386-2073
Combinatorial Chemistry &
High Throughput Screening
Volume 8, Number 7, November 2005
Contents
Editorial Pp. 553
Prospects for Combinatorial Chemistry in the Agrosciences
Pp. 555
Stephen D. Lindell and Jürgen Scherkenbeck
[Abstract]
Applications of Combinatorial Chemistry in the
AgroSciences Pp. 563
Jürgen Scherkenbeck and Stephen Lindell
[Abstract]
Targeting Chemical Inputs and Optimising HTS for Agrochemical
Discovery Pp. 577
Stephen C. Smith, John S. Delaney, Michael P. Robinson
and Martin J. Rice
[Abstract]
High Throughput Screening in Agrochemical Research Pp.
589
Klaus Tietjen, Mark Drewes and Klaus Stenzel
[Abstract]
Recent Advances in Microwave-Assisted Combinatorial Synthesis
and Library Generation Pp. 595
Tim Lange and Stephen Lindell
[Abstract]
Synthesis and agrochemical screening of a library of natural
product-like bicyclo[2,2,2]octenones Pp. 607
Stephen C. Smith, Donald R. James, Matthew M. Abelman
and Graham J. Sexton
[Abstract]
Parallel, Solution Phase Synthesis of Dihydropyridine
Miticides Via a Versatile Multicomponent Reaction Pp.
617
K. Cottrell, C.W. Holyoke, M. Kline, K.C. Lee, M.R. Nassirpour,
R.J. Pasteris and S. Shah
[Abstract]
The Design and Synthesis of a Herbicide Targeted Library
of N-[1- (1,3-Benzoxazol-2-yl)Alkyl]-6-Alkyl-1,3,5-Triazine-2,4-Diamines
Pp. 623
Hansjörg Dietrich, Wolfgang Giencke and Robert Klein
[Abstract]
Automated Synthesis & Purification at Bayer CropScience
Chemistry Frankfurt Pp. 631
Jürgen Zindel
[Abstract]
Solid Supported Synthesis of Phosphinates Via Palladium
(0) Catalysed Coupling Reactions Pp. 637
Klaus Haaf
[Abstract]
Communication: Polymer-Assisted Solution-Phase Synthesis
of 4,5-Dihydro-1, 4-Benzoxazepin-3(2H)-Ones Pp. 643
Ignacio Carreras, Jürgen Scherkenbeck and Christian
Paulitz
[Abstract]
The Design, Synthesis and Screening of a Muscarinic
Acetylcholine Receptor Targeted Compound Library Pp.
649
Jürgen Benting, Merisa Leonhardt, Stephen D. Lindell
and Jörg Tiebes
[Abstract]
Meet the Guest Editor (Jürgen Scherkenbeck) Pp.
655
[Abstract]
Meet the Guest Editor (Stephen D. Lindell) Pp.
656
[Abstract]
Abstracts
[Back to top]
Editorial
Since the appearance of the first reports during the early
nineties on non-peptidal small molecule libraries synthesized
on solid phase supports, the fields of combinatorial chemistry
and high throughput screening have experienced enormous progress
and development. These techniques have become an essential
part of the modern discovery process within the pharmaceutical
industry and many pharmaceutical companies, including AstraZeneca,
GlaxoSmithKline and Pfizer, are currently making major investments
in the area. This progress did not come without setbacks and
the biological screening results obtained from early combinatorial
libraries were often so disappointing that many companies
went though a period during which they seriously doubted whether
it would be possible to utilise these new techniques within
industry. However, even these bad results had value in that
they showed what not to do and today the pharmaceutical industry
seems to have learned how to more successfully apply these
powerful new tools to the drug discovery process.
The current situation and progress within the agrochemical
industry with regards combinatorial chemistry and high throughput
screening is not easy to determine. This is at least partly
because comparatively little has been published in the area
to date and what has been published is rather widely scattered
throughout the chemical literature. Progress in the area was
reviewed at the 2nd Pan-Pacific Conference on Pesticide Science
held in October 1999 in Honolulu, Hawaii [1] but since that
time no really comprehensive review has been published. This
special issue of Combinatorial Chemistry and High Throughput
Screening brings together a series of five review articles
whose purpose is to provide an up to date overview of the
current state of the art as relevant and applicable to the
agrosciences. In addition, seven research papers are being
published describing recent applications of high throughput
synthesis within the agrochemical discovery process. It is
hoped that the publication of these collected works in a single
issue will help facilitate informed debate about how best
to direct the vital research resources needed to ensure the
long term success of the agrochemical industry.
[1] Baker, D. R.; Umetsu, N. K.; Eds., ACS Symposium Series
774, “Agrochemical Discovery”, American Chemical
Society, Washington, DC, 2001. For a more recent review article
see, Smith, S. Pesticide Outlook, 2003, February, 21-25.
Jürgen Scherkenbeck
Bayer CropScience AG,
Global Chemistry Insecticides,
D-40789 Monheim,
Germany,
E-mail: juergen.scherkenbeck@bayercropscience.com
Stephen D. Lindell
Bayer CropScience GmbH,
Werk Höchst, G836,
D-65926 Frankfurt am Main,
Germany,
E-mail: Stephen.lindell@bayercropscience.com
[Back to top]
Prospects for Combinatorial Chemistry in the Agrosciences
Stephen D. Lindell and Jürgen Scherkenbeck
The recent progress and future prospects for the successful
application of combinatorial chemistry and high throughput
screening within the agrochemical lead discovery process are
outlined and discussed. Solid and solution phase library synthesis
technologies are reviewed and compared, and the role and importance
of bioavailability, diversity and virtual screening in rational
library design are detailed.
[Back to top]
Applications of Combinatorial Chemistry in the AgroSciences
Stephen D. Lindell and Jürgen Scherkenbeck
During the past ten years combinatorial chemistry developed
from a powerful synthetic methodology, providing large libraries
of usually simple new chemical entities, to a comprehensive
strategy presently covering a multitude of technologies across
the whole workflow from hit generation to lead optimization.
Thus combinatorial chemistry had a major impact not only on
the pharmaceutical research but also with some delay on the
agrochemical research. The agrochemical discovery environment
is different from that of the pharmaceutical research in that
it relies mainly on whole organism screenings. This review
summarizes some recent applications of combinatorial chemistry
in the agrosciences, covering all the three major fields of
research: Fungicides, herbicides, and insecticides. The article
focuses on libraries with published biological activities
and thus highlights some characteristic features of successful
agrochemical libraries, which may be fundamentally different
from pharmaceutical libraries.
[Back to top]
Targeting Chemical Inputs and Optimising HTS for Agrochemical
Discovery
Stephen C. Smith, John S. Delaney, Michael P. Robinson
and Martin J. Rice
In vivo high throughput screening (HTS) has been
adopted by most of the larger crop protection companies as
an important tool for the discovery of new agrochemicals.
There has been a paradigm shift in capabilities from screening
a few thousand compounds a year to several hundred thousand
and the quantity of screening sample required has fallen dramatically.
The unifying goal now bringing together screens and inputs
is the need to maximise the flow of useful information from
HTS and thereby minimise the time taken to discover robust
leads and new products. This review examines the positive
changes that have occurred towards targeted design and selection
of chemical inputs for agrochemical discovery over the last
ten years and corresponding developments in HTS assays, data
analysis and the logistics of compound storage and dispensing
[Back to top]
High Throughput Screening in Agrochemical Research
Klaus Tietjen, Mark Drewes and Klaus Stenzel
The demand for new herbicides, insecticides and fungicides
led to a steady increase in the number of compounds being
tested to find novel market products. To keep pace with the
rising workload, high throughput screening (HTS) technologies
have been introduced. In agrochemical research miniaturised
in vivo tests on whole real target organisms are now possible
and are an integral part of the screening cascade. A complementary
target based in vitro HTS has also been established in agrochemical
research. Target based HTS allows a directed approach towards
untouched market shares by novel modes of action. Selection
of the best suited targets is the most crucial issue in this
approach. Genomic methods thereby deliver many essential genes
as candidate targets. Consideration of further criteria such
as druggability notably narrows down the number of promising
targets. Though target to hit to lead progression still is
as in pharmaceutical research a complex and therefore risky
process, the implementation of novel bioscience technologies
has entailed the transition to an integrated innovative agrochemical
research perspective.
[Back to top]
Recent Advances in Microwave-Assisted Combinatorial
Synthesis and Library Generation
Tim Lange and Stephen Lindell
Progress and developments made in microwave-assisted combinatorial
synthesis and library production since 2002 are reviewed.
The use of microwave technology in both solution and solid
phase synthesis is discussed with special reference to agrochemical
applications where appropriate.
[Back to top]
Synthesis and agrochemical screening of a library
of natural product-like bicyclo[2,2,2]octenones
Stephen C. Smith, Donald R. James, Matthew M. Abelman
and Graham J. Sexton
A general route to a series of differentially substituted
bicyclo[2,2,2]octenones has been developed, making use of
the in situ intramolecular Diels Alder reaction of masked
ortho-benzoquinones. This approach was used to synthesize
a series of thirteen key acid-containing templates from which
a solution phase discovery library of 1126 diverse amides
was then constructed. The rigid polycyclic nature of the templates
and the prevalence of oxygenated functionality confer natural
product-like qualities and three-dimensional diversity. The
library was screened in HTS in vivo against a number of weed,
insect and fungal model organisms leading to the discovery
of a novel series of herbicidally active compounds. The development,
production and biological activity of the library are described.
[Back to top]
Parallel, Solution Phase Synthesis of Dihydropyridine
Miticides Via a Versatile Multicomponent Reaction
K. Cottrell, C.W. Holyoke, M. Kline, K.C. Lee, M.R. Nassirpour,
R.J. Pasteris and S. Shah
A novel class of highly active dihydropyridine miticides
was prepared using a multicomponent reaction process. The
initial lead was rapidly optimized using solution phase parallel
synthesis techniques and a positional scanning approach. Detailed
structure-activity relationships were developed for the amino
and carbonyl components of the molecule and used to select
the best candidates for broad field testing. The chemistry,
biology and toxicology of these compounds will be presented
along with numerous structural variants of the reaction products.
[Back to top]
The Design and Synthesis of a Herbicide Targeted Library
of N-[1-(1,3-Benzoxazol-2-yl)Alkyl]-6-Alkyl-1,3,5-Triazine-2,4-Diamines
Hansjörg Dietrich, Wolfgang Giencke and Robert Klein
Amino acids were immobilised by attaching them via a carbamate
linker to Wang resin. These intermediates were converted to1-(1,3-benzoxazol-2-yl)alkanamines
over three steps, followed by coupling with 4-alkyl-6-chloro-1,3,5-triazine-2-amines
to furnish the desired N-[1-(1,3-benzoxazol-2-yl)alkyl]-6-alkyl-1,3,5-triazine-2,4-diamines.
Physico-chemical property profiles were used to support design
and development of a combinatorial library. The synthetic
methodology described herein was validated with the production
of a herbicide targeted library of 300 members.
[Back to top]
Automated Synthesis & Purification at Bayer CropScience
Chemistry Frankfurt
Jürgen Zindel
The Automated Synthesis & Purification team at Bayer
CropScience in Frankfurt provides services and support in
the areas of synthesis and post synthesis activities for chemists.
This article describes our workflow and the special robotic
systems used. We produce small to medium sized compound libraries
using liquid phase techniques. An example of a compound library
taken from the herbicide area is given.
[Back to top]
Solid Supported Synthesis of Phosphinates Via Palladium
(0) Catalysed Coupling Reactions
Klaus Haaf
In order to gain a broad access to phosphinic acid derivatives,
a palladium catalysed coupling reaction of aryl iodides with
hypophosphorous acid derivatives has been developed on the
solid phase. The resulting arylphosphorous acids (or esters)
were derivatised using addition reactions with aldehydes,
imines and isocyanates, to give phosphinic acids (or esters)
with a-hydroxy , α–amino
or aminoacyl groups attached to the aryl phosphorus moiety.
This approach provided a broad chemical entry into a class
of polar phosphinates compounds which were rather difficult
to handle using normal solution phase synthesis. The synthetic
potential of this solid phase based methodology was demonstrated
by the synthesis of targeted libraries against the enzyme
dihydrodipicolinate synthase (DHDPS).
[Back to top]
Communication: Polymer-Assisted Solution-Phase Synthesis
of 4,5-Dihydro-1,4-Benzoxazepin-3(2H)-Ones
Ignacio Carreras, Jürgen Scherkenbeck and Christian
Paulitz
The polymer assisted solution phase (PASP) synthesis of
4,5-dihydro-1,4-benzoxazepin-3(2H)-ones is described. Using
salicylic aldehydes, a-bromo acetic acid esters, and primary
amines as broadly variable building blocks, the target molecules
were obtained in a straightforward manner. The use of polymer
bound reagents and scavengers greatly simplified workup, and
avoided the use of protecting groups. A small library was
prepared, showing the feasibility of the synthetic concept
for the generation of larger sets of screening compounds.
[Back to top]
The Design, Synthesis and Screening of a Muscarinic
Acetylcholine Receptor Targeted Compound Library
Jürgen Benting, Merisa Leonhardt, Stephen D. Lindell
and Jörg Tiebes
Potent new agonists of the insect muscarinic acetylcholine
receptor (mAChR) have been discovered by synthesizing and
screening a library of 225 oxime ether amines. Library evaluation
was facilitated by the development of a high throughput test
enabling the rapid determination of muscarinic agonist activity.
The most interesting compounds were the thiadiazole 17 and
the isoxazole 24 which were potent muscarinic agonists (EC50
13 and 21 nM, respectively) and showed lead levels of insecticidal
activity.
[Back to top]
Meet The Guest Editor
Jürgen Scherkenbeck was born in Remscheid, Germany in
1960 and obtained his diploma degree in chemistry from the
Ruhr-University Bochum in 1985. His doctoral work in the field
of natural product synthesis was performed under the supervision
of Professor Peter Welzel at Bochum. In 1988 he took up a
position within Central Research at Bayer AG in Leverkusen.
During his industrial research career he has been involved
in diverse research areas, including pheromone synthesis,
peptide chemistry and combinatorial chemistry. From 1999 to
2000, he spent one year as an Associate Professor at the Hong
Kong University of Science and Technology and following his
return to Central Research, he became head of the Combinatorial
Chemistry Department. In 2002 he moved to Bayer CropScience
where he is currently head of an insecticide chemistry group.
He is author or co-author of around 70 scientific papers and
patents and holds an honorary professorship at the University
of Leipzig.
Jürgen Scherkenbeck
[Back to top]
Meet The Guest Editor
Stephen Lindell was born in Ipswich, England in 1955 and
obtained his bachelors degree in chemistry from Imperial College,
London in 1977. His doctoral work was performed at the Research
Institute for Medicine and Chemistry in Cambridge, Massachusetts
under the supervision of Professor Sir Derek Barton and Dr.
Robert Hesse. In 1982 he moved to Stanford University in Palo
Alto, California to undertake post doctoral research with
Professor William Johnson. He returned to England in 1985
to take up a position with Schering Agrochemicals at their
Chesterford Park research site near Cambridge. In 1996, he
moved to the Companies Frankfurt-Hoechst research site in
Germany to work first with AgrEvo, then Aventis CropScience
and since 2002, with Bayer CropScience. During his industrial
research career he has been involved in the design and synthesis
of novel biologically active molecules in all three indications;
fungicides, herbicides and insecticides. He is author or co-author
of over 50 scientific papers and patents and is currently
head of the Hit Generation Chemistry Group at Bayer CropScience
in Frankfurt.
Stephen Lindell
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