Coban, Tomris (2020) Synthesis and evalutation of novel anthracene acrylamides and imines as G-quadruplex ligands for the treatment of cancer. (PhD thesis), Kingston University, .
Abstract
G-quadruplex ligands, which can intercalate the G-quadruplex structures, have been studied as a strategy for indirect inhibition of telomerase activity, alongside targeting other G-quadruplexes found in other genes, including oncogenes. The scope of G-quadruplex ligands as cancer targeting drugs is particularly high as there more than 350000 DNA sequences within the human genome that can be targeted. In light of this, several small molecules have been introduced, which can induce and stabilise G-quadruplexes, which are classified as new drug agents for cancer therapy. This thesis looks at the synthesis of suitably functionalised polyaromatic compounds to achieve this stabilisation. Deoxyribonucleic acid (DNA) in our cells contains the instructions for all aspects of life, from cell division to immune responses. The discoveries and structural determination of DNA, leading to the human genome project, provides a great resource for genetic understanding. The pairing of nuclear bases is typically represented as Watson-Crick. When DNA is chemically changed, disruption to cell processes occurs. Cancer is one outcome of this damage, where DNA is damaged to a point where cell cycle control is incapacitated. One key aspect of cancer is that cells lose the ability to undergo apoptosis. Telomeres are integral structures present in the DNA of eukaryotic cells. They consist of regions of DNA motifs that are repeated throughout the structure. These conserved motifs contain an abundance of Guanine in sequences of 3-4 repeat units. These Guanine units make up the Guanine tetrad structures that allow the telomere to function as genomic stabiliser and protective agent against DNA damage or cross chromosome fusion such that all telomeres have a single stranded Guanine motif overhang at the 3’ end of the chromosome. Telomere length will usually dictate the lifespan of a cell, however in cancer cells we see this mechanism for programmed cell death, hijacked by the expression of telomerase, which extends telomere length and inhibits programmed cell death. The well-established principle behind the development of G quadruplex ligands is that inhibition of telomerase, which isn’t expressed in healthy cells, can selectively facilitate apoptosis of cancerous cells. G-quadruplexes are structures that have shown the potential as therapeutic targets through 5 their propensity to associate with themselves and structures that are similar which will intercalate. Because of this, small molecules that intercalate within the structure and stabilise them within DNA have targeted G-quadruplexes. This stabilised DNA G-quadruplex structure will then inhibit the division of the cell through prevention of unwrapping and recognition of regulation regions and telomeric regions, which are normally cleaved off . In this research we aimed to make a number of G-quadruplex ligands to specifically target this inhibition and show activity against the HeLa cancer cell line. Throughout the research we synthesised several G-quadruplex ligands with different synthetic methodologies. Our success with these ligands was mainly achieved with imine couplings and these compounds showed cytotoxicity to HeLa cells. Compounds that showed cytotoxicity were further analysed for drug G-quadruplex interaction by 1D, 1H NMR titration experiments. Five of the compounds that showed cytotoxic effect demonstrated drug G-quadruplex interactions.
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