Synthesis and Characterisation of Dual CCR7/CXCR4 Antagonists

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.

URI

http://hdl.handle.net/10454/19272

Type

Thesis

Qualification name

PhD