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Biomedical subjects

Rolf Breinbauer

Publications and source records attributed to Rolf Breinbauer.

12 recordsLinked to original sources
PubMed2006

A generic building block for C- and N-terminal protein-labeling and protein-immobilization.

Expressed protein ligation (EPL) and bioconjugation based on the maleimide group (MIC-conjugation) provide powerful tools for protein modification. In the light of the importance of site-selectively modified proteins for the study of protein function, a flexible method for the introduction of tags and reporter groups into the C-terminus of proteins employing EPL and MIC-conjugation was developed. We describe the solid-phase synthesis of a generic building block, equipped with fluorescence markers or different functional groups. This generic building block allows for a flexible incorporation of different tags into proteins and was used for the introduction of fluorescence markers into the C-terminus of Rab and Ras GTPases by EPL or MIC-conjugation techniques. In addition, a building block appropriately modified for the incorporation of an azide into proteins was synthesized. Azide-functionalized Ras protein was immobilized on a phosphane-modified surface by means of Staudinger ligation providing a highly chemoselective ligation method for the immobilization of proteins.

Azides↗
PubMed2006

Electrolysis as an efficient key step in the homogeneous polymer-supported synthesis of N-substituted pyrroles.

[reaction: see text]. An efficient and general route to the soluble polymer-assisted synthesis of a set of 14 different N-substituted pyrroles using dendritic polyglycerol as a high-loading support is presented. The transformation of furan to the key intermediate 2,5-dialkoxytetrahydrofuran was performed by electrochemical oxidation followed by catalytic hydrogenation with Pt/C in high yield. Both reactions required heterogeneous reagents which can be conveniently used with polyglycerol as a soluble support.

Electrolysis↗
PubMed2005

Solid-supported reagents and catalysts for the preparation of large ring compounds.

Parallel combinatorial synthesis in solution using immobilized reagents, catalysts, and scavengers has emerged as a powerful technique for the preparation of diverse libraries of compounds. This technique has only recently been applied to the synthesis of large-ring compounds. In this comprehensive review several strategies are presented and discussed, including Pd-catalyzed allylic alkylation, Stille-coupling, macrolactonization and macrolactamization using solid supported reagents and catalysts. In several cases site isolation has allowed operation, of these macrocyclization reactions in concentrated solution (pseudo-dilution effect).

Catalysis↗
PubMed2004

The Staudinger ligation-a gift to chemical biology.

Although the reaction between an azide and a phosphane to form an aza-ylide was discovered by Hermann Staudinger more than 80 years ago and has found widespread application in organic synthesis, its potential as a highly chemoselective ligation method for the preparation of bioconjugates has been recognized only recently. As the two reaction partners are bioorthogonal to almost all functionalities that exist in biological systems and react at room temperature in an aqueous environment, the Staudinger ligation has even found application in the complex environment of living cells. Herein we describe the current state of knowledge on this reaction and its application both for the preparation of bioconjugates and as a ligation method in chemical biology.

Azides↗
PubMed2003

Protein structure similarity as guiding principle for combinatorial library design.

Proteins are modularly built from a limited set of approximately 1000 structural domains. The evolutionary relationship within a domain family suggests that the knowledge about a common fold structure can be exploited for the design of small molecule libraries in the development of inhibitors and ligands. This principle has been used for the synthesis of inhibitors for kinases sharing the same fold. It can also be applied for proteins which share the same fold architecture yet belong to different functional classes. Bestatin--originally known as an aminopeptidase inhibitor--was employed as guiding structure for the development of leukotriene A4 hydrolase inhibitors. A combinatorial approach helped to identify inhibitors for sulfotransferases which share structural similarity with nucleotide kinases using a kinase inhibitor core structure as guiding principle.

Combinatorial Chemistry Techniques↗
PubMed2002

From protein domains to drug candidates-natural products as guiding principles in the design and synthesis of compound libraries.

In the continuing effort to find small molecules that alter protein function and ultimately might lead to new drugs, combinatorial chemistry has emerged as a very powerful tool. Contrary to original expectations that large libraries would result in the discovery of many hit and lead structures, it has been recognized that the biological relevance, design, and diversity of the library are more important. As the universe of conceivable compounds is almost infinite, the question arises: where is a biologically validated starting point from which to build a combinatorial library? Nature itself might provide an answer: natural products have been evolved to bind to proteins. Recent results in structural biology and bioinformatics indicate that the number of distinct protein families and folds is fairly limited. Often the same structural domain is used by many proteins in a more or less modified form created by divergent evolution. Recent progress in solid-phase organic synthesis has enabled the synthesis of combinatorial libraries based on the structure of complex natural products. It can be envisioned that natural-product-based combinatorial synthesis may permit hit or lead compounds to be found with enhanced probability and quality.

Binding Sites↗
PubMed2002

Natural product guided compound library development.

Natural products are biologically validated starting points for the design of combinatorial libraries, as they have a proven record of biological relevance. This special role of natural products in medicinal chemistry and chemical biology can be interpreted in the light of new insights about the domain architecture of proteins gained by structural biology and bioinformatics. In order to fulfil the specific requirements of the individual binding pocket within a domain family it is necessary to optimise the natural product structure by chemical variation. Solid-phase chemistry is becoming an efficient tool for this optimisation process, and recent advances in this field are highlighted in this review article.

Binding Sites↗