Signal transduction cascades in living systems are commonly controlled via posttranslational
phosphorylation and dephosphorylation of proteins. These
processes are catalyzed and controlled in vivo by the action of kinase and
phosphatase enzymes, which consequently play an important role in many
disease states, including cancer and immune system disorders. Current
techniques for phosphoproteome analysis (using isotopic labelling,
chromatographic purification and phosphospecific antibodies) are undoubtedly
very powerful, however, these approaches have yet to provide a generally
applicable tool for phosphoproteome analysis despite the widespread utility such
a technique would have.
The use of small molecule organic catalysts capable of promoting selective
phosphate esterification would provide an extremely useful alternative to these
current techniques for use in, e.g. the labelling and pull-down of phosphorylated
proteins.
This thesis describes the development of aryl-N-oxide catalysts capable of
promoting site selective phosphorylation of polyol and peptide derivatives.
Whilst, ultimately, it was shown that these catalysts are not optimal for achieving
selective phosphate esterification in biological systems, an alternate synthetic
tool for phosphoproteomic analysis was developed. Progress in the development
of this pyrophosphorylate, eliminate, tag (pPET) strategy and its current
applications are discussed.