Linkers light-cleavable

Primary and secondary aliphatic amines can be linked to polymeric supports by acid-labile linkers or by linkers sensitive to nucleophiles. Linkers cleavable by light or by transition metal catalysis have also been described. The main types of linker for amines are sketched in Figure 3.24. 

I he standard analytical construct used for library production in Diversity Sciences at GlaxoSmithKline is shown in Figure 8.1. The analytical construct uses the common Knorr acid cleavable linkers at the first and second linker positions. The terminal linker is photocleavable and is released upon exposure to 350-nM light [12-15]. The construct contains the mass-code block and uses isotopically labeled Gly as a peak splitting element to facilitate compound identification by mass spectrometry. Also, the construct has two lysine amino acid groups to aid the ionization process of both the code block and the ligand... 

Generally, the electrocyclic cycloaddition reactions are performed thermally, without catalysis. Diels-Alder reactions are further facilitated by high pressure in hydrophobic structures, suffering hydrophobic collapse within an aqueous environment. Photochemical cycloadditions are often limited by the penetration of the polymeric support by the light of the desired wavelength. However, especially in case of hetero Diels-Alder reactions, Lewis acid catalysis has been applied. On a solid support the use of acid catalysis is often limited by the stability of the support linker, since most common linkers have been designed to be cleavable under acidic conditions. Table 4 shows some of the Lewis acids and the support link used. 

Due to a very low capacity of the glass surface, traditional analytical tools cannot be used for adequate assessment of fidelity of the light-directed synthesis. A highly sensitive analytical method to characterize quality of peptides synthesized by this technology was developed [43]. This involves derivatization of the surface with an acid-cleavable Knorr linker (Fig. 16 1) followed by the attachment of a C-terminal chromophoric tag, Lys(Dabs) (Fig. 16 2). 

A second generation of the tag, cICAT, was developed where C was used instead of and an acid-cleavable site was introduced into the linker. In contrast to and N, C-labeled peptides have identical retention times compared to the light isotope version, and the removal of the biotin moiety increased the spread in reversed-phase LC by a factor of three. The tagging method has been used in a large number of studies in a range of organisms, including bacteria, yeast, maize, mouse, and humans. ... 

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