Towards the synthesis of novel protein phosphatase inhibitors.
PhD thesis, University of Glasgow.
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Protein phosphatases (PPases) are important enzymes which mediate dephosphorylation of proteins in eukaryotic cells. These enzymes are involved in a variety of cellular processes, and disruption of their activity has been shown to be involved in the development of diseases such as cancers and Alzheimer’s. Protein phosphatase inhibitors (PPIs) have been used to regulate the activity of these enzymes, and hence, control the development of the cellular processes related to them. However, the lack of potent and selective readily accessible PPIs is a major obstacle to the understanding of these complex biological pathways, and the development of reliable synthetic routes towards new PPIs has therefore generated a significant amount of interest.
Several naturally occurring PPIs possess the “ADDA” residue , which has been shown to be crucial for their inhibitory activity. We would like here to report the synthesis of “ADDA”-isoforms such as enantio-ADDA 1 and enantio-iso-ADDA 2 through a convergent approach taking advantage of cross-metathesis methodology, non-aldol aldol and aza-Claisen rearrangements, as well as β-lactam chemistry.
We envisage using our synthetic approaches as a platform to generate a wide range of novel “ADDA”-containing analogues, which might lead to the discovery of potent and selective PPIs, which could be generated in multi-gram scale.
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