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Title: The development of new tools for high-throughput-synthesis and high-throughput-screening
Author: Valeur, Eric
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2006
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There are many strategies used in high-throughput-synthesis and one technique, based on the use of polymer-supported reagents in solution-phase, has evolved considerably over the past decade. However, only a limited number of efficient polymer-supported coupling reagents have been reported and many of them offer serious drawbacks, unlike their solution-phase equivalents. A comparison between common coupling reagents (IIDQ, HATU, PyAOP and BOP-CI) was therefore carried out and revealed that IIDGQ was the reagent of choice in the absence of the activation step. Polymer-supported IIDQ was therefore targeted.  This reagent performed better than commercially available HATU and all supported carbodiimides. Scope and limitation studies proved that the reagent was a versatile tool for the synthesis of amides from carboxylic acids and amines, including hindered substrates, secondary amines and anilines. A new strategy for the high-throughput-screening of small-molecules was developed. Microarrays are a powerful method to test quickly a wide range of small molecules against biological targets. In parallel, fragment-based drug discovery has boomed in the past decade. The combination of the two principles gave birth to the new concept of dual fragment microarrays. The technology was developed and evaluated using fragments known to bind to the human FK506-binding protein. These fragments were synthesised in solution-phase, then linked to a PNA tag synthesised on solid-phase, followed by release into stock solution and hybridisation onto DNA microarrays. Screening the arrays of mixtures of two fragments revealed that the expected strongest “dual” interaction was detected as the most intense spot, and thus validated the concept of dual fragment microarrays.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available