Alonso, Francisco Cuenca; (2008) Synthesis and evaluation of G-quadruplex DNA targeting agents. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The DNA at the telomeres and promoter regions of eukaryotic genes is G-rich and may form special DNA structures termed G-quadruplexes. These structures have high stability and there is evidence of their existence in vivo. G-quadruplexes in telomeric DNA can inhibit telomerase and potentially affect the architecture of telomeres, whereas their presence in promoter regions can inhibit gene expression. Telomere maintenance and oncogenes such as c-kit are recognised targets in anti-cancer therapy. G-quadruplex stabilisation by small molecules can selectively affect cancer cell viability by affecting telomere maintenance and the expression of c-kit and other oncogenes. The work in this thesis describes the design and synthesis of two families of novel G- quadruplex ligands and their evaluation as G-quadruplex stabilising agents and telomerase inhibitors and their preliminary biological evaluation as anti-cancer agents. The syntheses of two libraries, one composed by eighteen novel 4,5-disubstituted acridones and the other by twenty-two novel tri- and tetra-substituted naphthalene diimides, is discussed together with SAR analyses. The assessment of the DNA binding ability of the ligands was conducted using fluorescence resonance energy transfer (FRET) DNA melting experiments and surface plasmon resonance (SPR) binding studies. The evaluation of their telomerase inhibitory ability was performed using a modified telomerase repeat amplification protocol (TRAP) assay. The preliminary biological evaluation of the compounds consisted of cell culture studies using cancer and normal cell lines to assess their cell growth inhibitory ability and to give an insight into their mechanism of action.

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