eCombiChem Leads

Combinatorial Screening of Polymeric Coating Formulations

Jaime Grunlan, Senior Research Engineer, Avery Research Centre, will present the following seminar at the eCombiChem “Cutting Edge Technologies in Combinatorial Chemistry” Web Conference running at http://ecombichem.com/, and opening 20th September 2004:

Combinatorial Screening of Polymeric Coating Formulations

A combinatorial factory for the preparation and screening of polymeric coatings is outlined here. The coating formulations are prepared and coated using a novel combinatorial coating technique to obtain combinatorial libraries of varying composition and thickness. The thickness of each film in a combinatorial array is rapidly determined via visible-light absorbance of optical dyes in conjunction with the Beer-Lambert relationship. These combinatorial libraries are then tested and screened using a variety of custom-made high-throughput methods. Combinatorial screening of oxygen and moisture transmission rate, along with pressure-sensitive adhesive properties, is presented. OTR and MVTR are determined using spectrometric techniques. For adhesion, a spherical probe adhesive tester is able to generate parameters linked to tack, peel, and shear in one measurement. In addition to describing the testing methodology, benefits and shortcomings of these techniques will be highlighted.

Barry Hardy
Douglas Connect
www.douglasconnect.com
Cutting Edge Technologies in Combinatorial Chemistry: http://ecombichem.com/
ECombiChemLeads Blog: http://barryhardy.blogs.com/ecombichemleads/

Utilizing SynPhase Scavenger Lantern Technology for the Synthesis of Small Molecule Combinatorial Libraries via solution-phase methodologies

Nicholas Ede, Head of the Discovery Products business unit of Mimotopes, will present the following seminar at the eCombiChem “Cutting Edge Technologies in Combinatorial Chemistry” Web Conference running at http://ecombichem.com/, and opening 20th September 2004:

Utilizing SynPhase (TM) Scavenger Lantern Technology for the Synthesis of Small Molecule Combinatorial Libraries via solution-phase methodologies

Scavenging of unwanted reagents/reactants from solution phase reaction mixtures has emerged as an important alternative to contemporary purification of reaction mixtures in combinatorial chemistry. This allows for the parallel synthesis of large number of compounds in solution phase rapidly.

Mimotopes have designed and prepared several high loading Lanterns for use in scavenging applications. Combining the handling advantages with excellent scavenging capabilities, these new scavenger Lanterns are ideally suited for solution phase synthesis, particularly in a high throughput array format. This presentation will highlight a number of examples where scavenger Lanterns are used to make interesting drug-like compounds from, for example, Maybridge Reactive Intermediates such as 3,5-dimethylisoxazole-4-sulfonyl chloride. In addition, a simple and convenient solid phase synthesis of disubstituted guanidines which utilises the TMI-isocyanate SynPhase scavenger lantern 1 as a starting point will be presented (see Scheme below).

Barry Hardy
Douglas Connect
www.douglasconnect.com
Cutting Edge Technologies in Combinatorial Chemistry: http://ecombichem.com/
eCombiChemLeads Blog: http://barryhardy.blogs.com/ecombichemleads/

New Linkers and Polymer-supported Reagents for Organic Synthesis

Dr. A. Ganesan, School of Chemistry, University of Southampton, UK will present the following seminar at the eCombiChem “Cutting Edge Technologies in Combinatorial Chemistry” Web Conference running at http://ecombichem.com/, and opening 20th September 2004:

New Linkers and Polymer-supported Reagents for Organic Synthesis

The implementation of parallel chemistry demands new reagents for synthesis that are convenient and practical for high-throughput usage. At the same time, such tools must be robust and inexpensive. In this presentation, I will highlight two recent examples from our group. The first is a tetrafluoroarylsulfonate linker for solid-phase synthesis. It behaves as a ‘triflate' equivalent, and is suitable for both ‘traceless' cleavage as well as cleavage by Pd(0) catalyzed C-C bond forming reactions. The second application, for solution-phase synthesis, features cyclooctadiene immobilized on polystyrene at a high loading. This reagent functions as an electrophilic scavenger, and is readily converted to a polymer-supported version of the hydroborating reagent 9-BBN.

Barry Hardy
Douglas Connect
www.douglasconnect.com
Cutting Edge Technologies in Combinatorial Chemistry: http://ecombichem.com/
eCombiChemLeads – Blog on CombiChem News: http://barryhardy.blogs.com/ecombichemleads/

Drug Discovery by systematically scanning molecular space

Bernd Becker, Senior Research Scientist at Alchemia, will present the following seminar at the eCombiChem “Cutting Edge Technologies in Combinatorial Chemistry” Web Conference running at http://ecombichem.com/, and opening 20th September 2004:

Drug Discovery by systematically scanning molecular space

Molecular recognition between a ligand and its receptor, is generally dictated by the correct three-dimensional presentation of the ‘essential' functionalities of the ligand to the receptor binding site. Peptidomimetic drug discovery involves mimicking those functionalities and their bioactive presentation. Current libraries are often limited in their ability to truly scan molecular space in search for the correct three-dimensional presentation, due to restrictions imposed by the scaffolds used. Carbohydrates present a family of naturally occurring scaffolds with easily manipulated hydroxy functionalities in a variety of orientations. By carefully selecting a series of orthogonally protected scaffolds these can be decorated with a variety of substituents in different ring-positions and orientations (axial/equatorial) to find the optimal presentation required for recognition.

This approach was applied to the design and synthesis of a library targeting a group of G-protein coupled receptors with a common recognition motive, including somatostatin and melanocortin receptors. The resulting library contained a large number of compounds that were highly active and selective for different receptors within the group.

Barry Hardy
Douglas Connect
www.douglasconnect.com
Cutting Edge Technologies in Combinatorial Chemistry: http://ecombichem.com/
eCombiChem Leads: http://barryhardy.blogs.com/ecombichemleads/

Application of microchannel flowreactors for lead optimization and library development

Ferenc Darvas, Ph.D., President and Chairman, ComGenex, Inc. will present the following seminar at the eCombiChem “Cutting Edge Technologies in Combinatorial Chemistry” Web Conference running at http://ecombichem.com/, and opening 20th September 2004:

Application of microchannel flowreactors for lead optimization and library development

Combinatorial chemistry is a target/oriented, adaptive science that is now facing the challenge of fast developing fields such as micro and nanotechnologies. The drive towards miniaturization has several advantages, namely speed, increased reaction sensitivity and control and cost effectiveness.

An important development has been the utilization of microfabricated devices such as microchannel flow reactors for synthesis of general and focused libraries as well as for lead optimization. These micro devices can be defined as a series of minute interconnecting channel reactors in which chemical reactions are performed in a continuous flow. Continuous methods are widely used in chemical synthesis due to their lower operating costs and high efficiency, their main drawbacks being size, high set up costs and lack of flexibility. The development of continuous micro channel flowreactors has the potential to overcome these disadvantages due to their higher yields, and reaction selectivity and control, leading to an enhancement of both productivity and performance of combinatorial library synthesis, together with other unusual chemical and operation opportunities.

Microchannel flowreactors can perform standard homogenous, or heterogeneous, gas/solid/liquid phase reactions, which represent an efficient method for parallel synthesis of combinatorial libraries. A substantial increase of the reaction rate relative to the batch liquid phase reaction is generally achieved, thus allowing a faster synthesis of more and often highly purified compounds.

These microchannel flowreactors are safe and convenient to use in any laboratory and they are compatible with widely available robotic equipment. After a number of optimization rounds, the device can be used for any chemical synthesis under the desired conditions.

In this presentation an overview will be given on this rapidly developing field with specific examples as well as future trends described.

Barry Hardy
Douglas Connect
www.douglasconnect.com
Cutting Edge Technologies in Combinatorial Chemistry: http://ecombichem.com/

Target Class Library Design, Development and Production in Drug Discovery at Bristol-Myers Squibb

Christopher Cooper, Associate Director of New Leads Chemistry at Bristol-Myers Squibb, will present the following seminar at the eCombiChem “Cutting Edge Technologies in Combinatorial Chemistry” Web Conference running at http://ecombichem.com/, and opening 20th September 2004:

Target Class Library Design, Development and Production: Recent Applications of the IRORI NanoKan™ Combinatorial Chemistry System

The dynamic environment of exploratory and early phase drug discovery research across the pharmaceutical industry has necessitated re-evaluations of the established paradigms at the Bristol-Myers Squibb Pharmaceutical Research Institute. Efforts to capitalize on concurrent advances in genomics, high capacity combinatorial chemistry, and high-throughput screening have resulted in new strategic approaches to drug discovery. In the areas of parallel synthesis and combinatorial chemistry, New Leads Chemistry has developed a fully integrated suite of technologies to address the current and anticipated needs for the Institute. An overview of gene family target class library design, the establishment of target class knowledge databases, and the resulting development and production of target class-biased combinatorial libraries will be presented including recent successful applications of the state-of-the-art IRORI NanoKan™ Combinatorial Chemistry System.

Barry Hardy
Douglas Connect
www.douglasconnect.com
Cutting Edge Technologies in Combinatorial Chemistry: http://ecombichem.com/

High-Speed Microwave Chemistry: Enabling Technology in Solution and Solid-Phase Combinatorial Chemistry

Oliver Kappe, Professor of Chemistry at the Karl-Franzens-University in Graz, Austria and Editor of the Journal QSAR and Combinatorial Sciences, will present the following seminar at the eCombiChem “Cutting Edge Technologies in Combinatorial Chemistry” Web Conference running at http://ecombichem.com/, and opening 20th September 2004:

High-Speed Microwave Chemistry: Enabling Technology in Solution and Solid-Phase Combinatorial Chemistry

Microwaves have truly revolutionized "chemistry" in the kitchen during the past three decades. The rapid heating of foodstuffs in microwave ovens is nowadays used routinely by a significant proportion of mankind. Somewhat more recently (1986) the first pioneering reports on the use of microwave heating to carry out synthetic organic transformations were published independently by the groups of Gedye and Giguere/Majetich. It was soon realized that performing organic synthesis under microwave irradiation has some significant advantages as compared to classical heating techniques. Characteristically, microwaves generate rapid intense heating of polar substances with significant reductions in reaction times, cleaner reactions that are easier to work up, and in many cases higher yields.

Not surprisingly, these features have recently also attracted interest from the drug discovery/medicinal chemistry communities where reaction speed is of great importance. The combination of microwave heating technology and combinatorial chemistry applications therefore seems a logical consequence of the increased speed and effectiveness offered by using microwave irradiation instead of conventional heating methods. 3 The focus of this lecture will be on microwave-assisted solid-phase synthesis, multicomponent reactions, and solution-phase library generation strategies using automated sequential microwave irradiation techniques.

Barry Hardy
Douglas Connect
www.douglasconnect.com
Cutting Edge Technologies in Combinatorial Chemistry: http://ecombichem.com/

Fluorous synthesis, A new approach to solution-phase libraries

Wei Zhang, Director of Discovery Chemistry, Fluorous Technologies Inc., will present the following seminar at the eCombiChem “Cutting Edge Technologies in Combinatorial Chemistry” Web Conference running at http://ecombichem.com/, and opening 20th September 2004:

Fluorous synthesis, A new approach to solution-phase libraries

Methods to synthesize small molecules are in transition in many pharmaceutical and biotechnology companies. Some major trends are emerging: strong preference towards solution-phase parallel synthesis; high demand on molecular diversities for discovery libraries and small targeted libraries for lead optimization projects; increasing quantities (10-50 mg) and purities (>90%) for testing or deposition in compound collections. These requirements tax current solution-phase methodology to its limits because of time consuming separations. Fluorous Technologies, Inc. (FTI) is developing a broad-based technology platform that comprehensively addresses the demanding synthetic chemistry needs in the modern drug discovery environment.

Fluorous synthesis has been recently introduced as a “beadless” combinatorial technology. It employs perfluoroalkyl chains instead of resins as “phase tags” to facilitate the separation process. The separation is performed by strong and selective interactions between fluorous molecules with fluorous sorbents in solid-phase extraction or chromatography formats. Traditional solution-phase reaction conditions and facile phase-tag separations are successfully integrated into fluorous synthesis. Major advantages of fluorous synthesis include: fast homogeneous reaction kinetics ; easy purification by fluorous separations as well as conventional methods such as chromatography; no large excess of fluorous reagents required for the completion the of reaction; easy adoption of conventional reaction conditions; and recoverability of fluorous reagents.

This presentation describes the recent effort at FTI on the development of fluorous compounds including reagents (e.g. F-DEAD and F-phosphine for Mitsunobu reaction), scavengers (e.g. F-thiol for electrophiles, F-iscyanate and F-isatoic anhydride for nucleophiles), protecting groups (e.g. F-Boc, F-Cbz, F-Fmoc, and F-silanes), tags (e.g. F-FluoMar and F-sulfonyl fluoride), building blocks (e.g. F-amino acids), and their applications in the synthesis of drug-like molecules and natural product libraries including hydantoins, disubstituted primidines, and mappcines. Combination of fluorous synthesis with microwave technology for Pd-catalyzed coupling reactions, Ugi multi-component reactions, Biotage Horizon flash chromatography of big scale intermediates, and performance comparison with conventional solution-phase and solid-phase synthesis will also be highlighted.

Barry Hardy
Douglas Connect
www.douglasconnect.com
Cutting Edge Technologies in Combinatorial Chemistry: http://ecombichem.com/