Metastasis is a major cause of death in cancer patients but currently there are no
drugs available for its treatment. Hence there is an urgent clinical need for
identifying and developing anti-metastatic drugs. The activation of CC chemokine
receptor 7 (CCR7) and C-X-C chemokine receptor type 4 (CXCR4) plays an
important role in lymph node metastasis in a variety of cancers. Indeed, in
patients with tumours which are positive for CCR7 and/or CXCR4 expression,
prognosis and survival are poorer than those whose tumours are negative for
these receptors. CCR7 and/or CXCR4 activation, in addition to being involved in
inducing invasive phenotypes in cancer cells, promotes tumour cell growth and
survival. Our group has previously identified a series of sulfonamides as CCR7
antagonists. This project aims to extend on those studies and to develop a dual
CCR7 and CXCR4 antagonist to reduce metastasis in cancer.
Novel potent biaryl sulfonamide CCR7 antagonists were synthesised and
assessed by calcium flux assay. Several potential dual CCR7 and CXCR4 biaryl
sulfonamide antagonists have been synthesised, these are hybrid compounds
incorporating features from CCR7 antagonists of this project, and from known
sulfonamide CXCR4 antagonists. The most potent of such compound was able
to inhibit CCR7 activation in calcium flux assay (95% inhibition at 1 µM), however,
the relative potency of these compounds as CXCR4 antagonists was low. Molecular docking was used to investigate the binding mode of the synthesised
compounds in CCR7 and CXCR4. The generated docking poses were able to
rationalise some of the calcium flux assay results.
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/19272 |
| Date | January 2019 |
| Creators | Izidro, Mario C. |
| Contributors | Not named |
| Publisher | University of Bradford, Institute of Cancer Therapeutics. Faculty of Life Sciences |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Thesis, doctoral, PhD |
| Rights | <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>. |
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