Combinatorial chemistry linker

K. Gordon and S. Balasubramanian, Solid phase synthesis - designer linkers for combinatorial chemistry A review J Chem Technol Biotechnol 74 835-851 7999. 

F. Guillier, D. Grain and M. Bradley, Linkers and Cleavage Strategies in Solid-phase Organic Synthesis and Combinatorial Chemistry, Chem Rev 100 2091-2157 2000. 

One of the key technologies used in combinatorial chemistry is solid-phase organic synthesis (SPOS) [2], originally developed by Merrifield in 1963 for the synthesis of peptides [3]. In SPOS, a molecule (scaffold) is attached to a solid support, for example a polymer resin (Fig. 7.1). In general, resins are insoluble base polymers with a linker molecule attached. Often, spacers are included to reduce steric hindrance by the bulk of the resin. Linkers, on the other hand, are functional moieties, which allow the attachment and cleavage of scaffolds under controlled conditions. Subsequent chemistry is then carried out on the molecule attached to the support until, at the end of the often multistep synthesis, the desired molecule is released from the support. 

Keywords Combinatorial Chemistry m Solid-Phase Synthesis m Solid-Phase Scavenger m Linker m Targeted Library m Small Molecule Libraries... 

Fig. 18.3 Variation-based strategies. Left The SHAPES Linking Library [11] consists of drug-like scaffolds connected by linkers that are amenable to combinatorial chemistry (dashed line). Hits are followed up by synthesizing a combinatorial library in which the scaffolds are systematically varied. Center Directed Combinatorial Librari es [12] are comprised of scaffolds containing multiple sites for substituents. Hits are followed up by...

In general, organic chemistry on polymeric supports, which is the major tool in combinatorial chemistry with the implementation of organic compounds, can be divided into three parts the polymeric support, often a polystyrene resin the product, and the linker which enables a suitable connection between the two parts (Fig. 3.1) [5]. 

The design of powerful new linker strategies is crucial to the advancement of technologies used for combinatorial chemistry on polymeric supports. They are usually derived from protecting groups known for solution-phase chemistry [6, 18]. 

The triazene linker featured above is a traceless one that efficiently yields an aryl iodide upon treatment with methyl iodide. It is perhaps not well known to the combinatorial chemistry community. 

The first installment in this series (Volume 267, 1996) mostly covered peptide and peptidomimetic based research with just a few examples of small molecule libraries. In this volume we have compiled cutting-edge research in combinatorial chemistry, including divergent areas such as novel analytical techniques, microwave-assisted synthesis, novel linkers, and synthetic approaches in both solid-phase and polymer-assisted synthesis of peptides, small molecules, and heterocyclic systems, as well as the application of these technologies to optimize molecular properties of scientific and commercial interest. 

Combination of microbiological chemistry, often yielding scaffolds not easily obtained by purely chemical means, and combinatorial chemistry, enabling rapid and efficient synthesis of analogs, provides a valuable tool for generation of novel test compounds. As an example [24] we describe here the application of our lipoic acid-derived thioketal linker [25] to the solid-phase synthesis of A4-3-keto steroidal ureas from / -sitosterol. 

Here, we would like to briefly discuss basic peculiarities of the solid matrices, the various categories of linkers and some reaction types of established significance for combinatorial chemistry. For more comprehensive compilations of solid-phase reactions, the reader is referred to specific reviews [1-5] and commercial electronic databases (e.g. SPORE [6] or SPS [7]). 

The use of dendrimers as soluble supports in combinatorial chemistry was recently introduced by Kim et al. [204] for the synthesis of a 27-member pool library of indoles (three pools by nine individuals). The structure of the dendritic support, which was prepared condensing the commercially available starburst polyamidoamine (PAMAM) dendrimer with the 4-hydroxymethyl benzoic acid (HMB) linker, is given in Figure 7.24. 

Felder E, Resins, linkers and reactions for solid phase synthesis of organic libraries, in Combinatorial Chemistry and Combinatorial Technologies Methods and Applications (Eds. G. Fassina, S. Miertus), chapter 6 pp. 89-106, 2005, this volume. 

While considerable efforts have been spent in the past few years in the field of solid supports for combinatorial chemistry [73], most of them were devoted to modified polystyrenic beads with different sizes, loadings or swelling properties [74], or carrying different functionalities or linkers for library synthesis [75], or to solid supports different from resin beads (pins [76], cellulose [77], soluble supports [78], and so on). Few reports dealt with labelled solid supports prepared by chemical reactions (see the previous paragraphs) and significant efforts in the field of material sciences to obtain intrinsically labeled, nonchemically encoded, easily readable, combinatorial solid supports have not been reported. 

Resins, Linkers, and Reactions for Solid-Phase Synthesis of Organic Libraries. Felder, E. R. In Combinatorial Chemistry and Technology Miertus, S.. Fassina, G., Eds. Dekker New York, 1999, pp 35-51. 

Key Words Acidolytic cleavage backbone amide linkage bioconjugate chemical ligation combinatorial chemistry handle linker peptide alcohol peptide aldehyde peptide ester peptide thioester protecting group solid support. 

GuilUer F, Orain D, Bradley M. Linkers and cleavage strategies in solid-phase organic synthesis and combinatorial chemistry. Chem. Rev. 2000 100 2091-2157. 

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