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Title: Design and synthesis of novel inhibitors of the p53-Mdm2 interaction and the development of novel inhibitors of cyclin dependent kinases
Author: Bailey, Kevin Roy
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2004
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The disruption of the p53-Mdm2 interaction is an attractive therapeutic strategy for activating p53 tumour suppressor activity in tumours expressing wild type p53. One such strategy for the disruption of the P53-Mdm2 interaction is the design of low molecular weight ligands that bind at the p53-Mdm2 interface. The molecular docking programme LIDEAUS has identified a sulphonamide scaffold that has the potential to bind at the p53-Mdm2 interface. Adopting a high-throughput, combinatorial chemistry approach, a number of sulfonamides and amide have been synthesized and screened in vitro for their ability to disrupt the p53-Mdm2 interaction. Cyclin dependent kinases (CDKs) are important in cell cycle regulation as they control the transition between the four primary phases. The association of a cyclin dependent kinase with a cyclin subunit, and subsequent phosphorylation of the complex formed, is essential for CDK activity. Therefore, the design of ATP antagonists that inhibit the activity of CDKs is an attractive strategy for the treatment of proliferative disorders. Using microwave assisted organic synthesis, a high-throughput synthetic sequence has been developed to afford a series of 6-anilino-4-aryl-pyrimidines (I) that have been subsequently screened in vitro against a panel of kinases. Several of these compounds have been shown to be low micromolar inhibitors of the CDK2/cyclin E complex.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available