Loading...
Design, Synthesis and Biological Evaluation of Inhibitors of Polysialyltransferases PST and STX. Design, synthesis and biological evaluation of a range of N-modified mannosamines, sialic acids and analogues from in silico screening as inhibitors of PolySia-NCAM biosynthesis with anti-migration activity.
Springett, Bradley R.
Springett, Bradley R.
Publication Date
2013
End of Embargo
Supervisor
Rights
The University of Bradford theses are licenced under a Creative Commons Licence.
Peer-Reviewed
Open Access status
Accepted for publication
Institution
University of Bradford
Department
Institute of Cancer Therapeutics, School of Life Sciences
Awarded
2013
Embargo end date
2027-03-05
Collections
Additional title
Abstract
Polysialylated NCAM (polySia-NCAM) is re-expressed in a number of tumours, including small cell lung carcinoma and neuroblastoma and is strongly associated with aggressive, invasive and metastatic tumours in the clinic. SiRNA knockdown of the polysialyltransferases (polySTs), the enzymes responsible for polysialylation of neural cell adhesion molecule (NCAM), has been shown to abolish cell migration. PolySia-NCAM is thus a highly attractive novel therapeutic target. A library of potential polyST inhibitors has been synthesised, using substrate-based design and computational chemistry. Compounds synthesised include N-acylmannosamine analogues, thio-linked CMP-sialic acid analogues, N-acyl modified sialic acids and compounds incorporating elements of both approaches. Novel methodology development in the synthesis of many of the compounds is described, notably a novel route to N-acyl sialosides. In addition, compounds identified from in silico screening were considered. Routes to synthesis and isolation of analogues of biologically active compounds are described. Using an enzyme assay, compounds were evaluated for their ability to reduce polySia synthesis through polyST inhibition. Effects of agents on polySia expression in cells, and the ability of compounds to reduce cell migration in vitro was studied using a wound healing ‘scratch assay’.
The data from these experiments revealed a number of potent modulators of polySia assembly and their efficacy in reducing cell migration, as well as the limits of the biosynthetic pathway to accept unnatural sialic acid precursors. This is the first example of polyST inhibition modulating tumour cell migration, and points to the potential of the polysialyltransferases as a therapeutic target in metastatic tumours.
Version
Citation
Link to publisher’s version
Link to published version
Link to Version of Record
Type
Thesis
Qualification name
PhD
Notes
The full text will be available at the end of the extended embargo: 5th March 2027