New linkers for the direct biological assay of combinatorial libraries

Abstract

Solid phase combinatorial libraries are primarily synthesised for screening against a biological target. This thesis describes the synthesis and evaluation of three safety-catch linkers, which allow cleavage of amines and alcohols from the solid phase in biologically compatible conditions.

The ability of these linkers to release alcohols was demonstrated through the synthesis and evaluation of models in solution and on the solid phase. Two of these linkers were shown to successfully release amines through the synthesis and evaluation of model compounds tested in solution. However these linkers were not demonstrated to be useful for cleaving hydroxamic acids from the solid phase.

The purpose of this technology was to facilitate the development of a novel high throughput screening technique known as the zone diffusion assay. This assay was designed to isolate active compounds rapidly from a combinatorial library. Studies towards this new assay are described, using gelatinase (the enzyme), gelatin (the substrate) and marimastat (a known hydroxamic acid inhibitor) and the principle was conclusively demonstrated. Due to the lack of the utility of these linkers to the cleavage of hydroxamic acids from the solid phase, the linkers were not successfully applied to the development of this assay.

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