Design and Synthesis of Acridine-Based Macrocyclic G-Quadruplex DNA Ligands

DNA sequences that are rich in the guanine nucleic base possess the ability to fold into higher order structures called G-quadruplexes. These higher level structures are formed as a result of two sets of four guanine bases hydrogen-bonding together in a planar arrangement called a guanine quartet. Guanine quartets subsequently stack upon each other to form quadruplexes. G-quadruplexes are mainly localized in telomeres as well as in oncogene promoters. One unique and promising therapeutic approach against cancer involves targeting and stabilizing G-quadruplexes with small molecules, generally in order to suppress oncogene expression and telomerase enzyme activity; the latter has been found to contribute to “out-of control” cell growth in ca. 80-85% of all cancer cells and primary tumours while being absent in normal somatic cells. In this work, we present efforts towards designing and synthesizing acridine-based macrocycles (Mh) and (Mb) with the purpose of providing potential G4 ligands that are suited for selective binding to G4 vs. duplex DNA, and stabilize G-quadruplex structures. Two ligands described in this study include an acridine core which provides an aromatic surface capable of π-π interactions with the surface of G-quadruplexes. The successful synthesis of 4,5-diaminoacridine is described in chapter 2, as an essential fragment of the macrocycles (Mh) and (Mb). In order to investigate the synthetic method for macrocyclization, model compounds composing almost half of the designed macrocycles were explored. As discussed in chapter 3, the synthesis of the model compound for (Mb) turned out to be challenging. However, as a step towards the synthesis of (Mh), the synthesis of the hydrogen-containing model compound, which is almost half of the desired macrocycle (Mh) was achieved in our group and proved to be promising.

Refractometry Studies of the Optical Properties of Polymer Films and the Development of Polymer Coated Refractive Index Sensors

Sensors for real-time monitoring of environmental contaminants are essential for protecting ecosystems and human health. Refractive index sensing is a non-selective technique that can be used to measure almost any analyte. Miniaturized refractive index sensors, such as silicon-on-insulator (SOI) microring resonators are one possible platform, but require coatings selective to the analytes of interest. A homemade prism refractometer is reported and used to characterize the interactions between polymer films and liquid or vapour-phase analytes. A camera was used to capture both Fresnel reflection and total internal reflection within the prism. For thin-films (d = 10 μm - 100 μm), interference fringes were also observed. Fourier analysis of the interferogram allowed for simultaneous extraction of the average refractive index and film thickness with accuracies of ∆n = 1-7 ×10-4 and ∆d < 3-5%. The refractive indices of 29 common organic solvents as well as aqueous solutions of sodium chloride, sucrose, ethylene glycol, glycerol, and dimethylsulfoxide were measured at λ = 1550 nm. These measurements will be useful for future calibrations of near-infrared refractive index sensors. A mathematical model is presented, where the concentration of analyte adsorbed in a film can be calculated from the refractive index and thickness changes during uptake. This model can be used with Fickian diffusion models to measure the diffusion coefficients through the bulk film and at the film-substrate interface. The diffusion of water and other organic solvents into SU-8 epoxy was explored using refractometry and the diffusion coefficient of water into SU-8 is presented. Exposure of soft baked SU-8 films to acetone, acetonitrile and methanol resulted in rapid delamination. The diffusion of volatile organic compound (VOC) vapours into polydimethylsiloxane and polydimethyl-co-polydiphenylsiloxane polymers was also studied using refractometry. Diffusion and partition coefficients are reported for several analytes. As a model system, polydimethyl-co-diphenylsiloxane films were coated onto SOI microring resonators. After the development of data acquisition software, coated devices were exposed to VOCs and the refractive index response was assessed. More studies with other polymers are required to test the viability of this platform for environmental sensing applications.