Date

2022-1-24

Author

Doğan, Kübra

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The use of small molecules as therapeutic agents opens up new possibilities for treating a variety of diseases, including cancer. A major class of chemotherapy agents act on cancer cells by altering or damaging the cell's DNA structure. G-quadruplexes (G4s) are a type of non-canonical DNA secondary structures that forms in guanine-rich regions. They are essential in regulation of transcription and translation, as well as telomere maintenance. Targeting G4s with small molecules has been a promising strategy in cancer research. Even though many small molecules are used in the treatment of different cancer types, there is still a need for the discovery of new ones that are more selective and less toxic to the cells. Within the scope of this thesis, in the first part, three new Azacyanine derivatives that might potentially be chemotherapeutic agents as DNA binding small molecules were synthesized and characterized. Nuclear Magnetic Resonance spectroscopy, UV-vis spectroscopy, Mass spectroscopy and Elemental Analysis were used for characterization. The extinction coefficients and quantum yields were calculated. After that, their interactions with different DNA structures were investigated using competition dialysis assay, UV-vis absorption and Circular Dichroism (CD) spectroscopy. Our investigations demonstrated that the synthesized Azacyanine derivatives have an affinity towards G4 structures, especially to Pu22, BCL-2, C-myc and VEGF. In the second part of this thesis, a fluorescent detection method for Hydroxychloroquine (HCQ) based on the interactions between Tel24 G4 structure and Thioflavin T was developed. HCQ, a medication used primarily to prevent and treat malaria, has many side effects including, cardiomyopathy and retinopathy. Accordingly, the development of simple, fast, and effective sensors is required for HCQ containing pharmaceuticals and biological samples. G4 based biosensors have received great attention in recent years due to their low detection limit, easy operation, rapid detection ability and high sensitivity. Here, a G4 based fluorescent sensor for HCQ detection was developed with the limit of detection (LOD) of 0.116 µM under the optimized conditions. The applicability of the developed method in real samples was assessed using human serum and urine samples. The average recoveries (%) were found to be in the range of 75-110% for human urine samples and 62-83% for human serum samples, which demonstrate the suitability of the proposed fluorometric method in detecting HCQ in different matrices.

Subject Keywords

G-quadruplex, Azacyanine, Hydroxychloroquine, Fluorometric Detection

URI

https://hdl.handle.net/11511/95960

Collections

Graduate School of Natural and Applied Sciences, Thesis