P-37: Cytotoxic Ureidoquinolines Affecting DNA and Telomerase


Vosough F *, Rasoul Amini S , Ghasemi Y ,

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Objective: Eucaryotic chromosome ends, consist of thousands of repeats of sequence TTAGGG, so-called Telomeric DNA, which has an important role in regulation of cell growth and replication. Telomeric DNA shortens with every cell division, and when it reaches a critical size, cell can no longer divide, hence ages and dies. One of the most compromising features of cancer cells is unlimited capacity of replication, which they acquire through overexpression of an enzyme called Telomerase. So, Telomerase is an ideal and attractive target for cancer drug development. According to the reported studies a variety of small molecule ligands including anthraquinon, porphyrin, acridine and quinoline structures have demonstrated their ability as Telomerase inhibitors. In this study the previously reported novel designed cytotoxic Ureidoquinolines were considered as DNA and Telomerase affecting ligands. Materials and Methods: The five novel Ureidoquinolines were initially designed using basic computational chemistry and molecular modeling. The designed Ureiodoquinolines were synthesized from their starting materials in about four steps. Then the behavior of the synthesized Ureiodoquinolines was studied toward DNA and Telomerase individually. The DNA interaction was evaluated on two sources of DNA using Gel electrophoresis, UV and fluorescence spectroscopy. Also, their effect on Telomerase and cell growth was investigated by TRAP assay and MTT assay. Results: The five synthesized Ureidoquinolines were confirmed by NMR and Mass spectrometry. The results of UV-visible and fluorescence spectroscopy provided evidence for their DNA interaction. The TRAP assay results showed their potency to affect Telomerase. The MTT studies on a type of breast cancer cell line (T47D) confirmed considerable cytotoxicity for the synthesized Ureidoquinolines in comparison to a couple of the common anticancer agents. Conclusion: Finally, the obtained results encourage us to introduce these novel designed Ureidoquinolines as cytotoxic lead compound affecting on DNA and Telomerase. Further studies on the Ureidoquinolines might help to have selective cytotoxic agents to overcome the common side effects on normal cells.