Targeting receptors and DNA secondary structures with small molecules and calix[4]arene conjugates

• Main Author: Sheng, Qiran
• Published: University of East Anglia 2016
• Subjects: 615.1
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.716397

This body of research is focused on developing calixarene conjugates targeting i-motif structures and integrin receptors. In Chapter 1, a general background of DNA secondary structures and i-motifs was described, mainly focused on the biological relevance, the experimental techniques and known interacting ligands in i-motif studies. In Chapter 2, a high-throughput i-motif ligand screen method was established, based on fluorescent intercalator displacement. Thiazole orange was used as the fluorescent intercalator in the screen against human telomeric i-motif. Its binding was studied using several spectroscopic techniques. A compound library was used to evaluate the newly developed high-throughput screen method using a plate reader and tobramycin was found as the most valuable hit compound in this screen. In Chapter 3, a family of water soluble, DNA-targeting calixarene conjugates were synthesis and characterised. They were functionalised with and DNA-binding moiety on the lower rim. It was found that two of the calixarene conjugates, 28 and 54, were able to condense G-quadruplex and i-motif forming sequences from human telomere and c-MYC promoter. The calixarene induced condensation was stable under acidic pH, but behave reversible by heating at neutral pH. Chapter 4 discussed the possibility to develop a calixarene based tumour recognising ligand. In order to achieve tumour targeting, a novel cyclic RGD peptide bearing alkyne was made and tested in the ‘click’ reaction. Later on, a route to conjugate the novel cyclic RGD peptide with a calixarene tethered with a fluorescent tag was established. It was found that a linker between calixarene and peptide moiety or the copper (I) catalyst was crucial in making this calixarene-peptide conjugate. Chapter 5 described the experimental procedures used in Chapter 2, 3 and 4. Chapter 6 summarised the key findings in Chapter 2, 3 and 4, as well as proposing the future work for all three chapters.