Template-assembled synthetic G-quartets as targets for anticancer drugs

by Bo Liu

Institution: University of British Columbia
Department: Chemistry
Degree: MS- MSc
Year: 2012
Record ID: 1983330
Full text PDF: http://hdl.handle.net/2429/42814


DNA is a classic target for small-molecule ligands. In order to reduce significant toxicities of anticancer drugs resulting from unspecific interactions with DNA duplexes, it aroused great interest to investigate the specific interactions of ligands with a secondary DNA structure, G-quadruplex, formed by a guanine-rich DNA sequence. Induction and stabilization of G-quadruplex structures by ligands have been shown to inhibit telomerase activities and regulate the transcription and expression levels of oncogenes in cancer cells; therefore, the design of synthetic G-quartets under physiological conditions as minimal models of G-quadruplexes or artificial receptors of anticancer drugs has become an important and promising approach to clarify binding mechanisms, as well as to develop practical high-performance anticancer drugs. This thesis explores the recognition behavior of the second generation of hydrophilic template-assembled synthetic G-quartets (TASQs) using fluorescence spectroscopy and CD spectroscopy with PIPER, TMPyP4, AZATRUX, BSU 1051 and BRACO-19. The results show that PIPER, TMPyP4, AZATRUX can stack on top of a G-tetrad plane via π-π stacking with stoichiometries of 1:1 and high binding affinities (KPIPER=1.65×10⁷ M⁻¹, KTMPyP4= 8.5×10⁵ M⁻¹, KAZATRUX=2.55×10⁶ M⁻¹); however, BSU 1051 and BRACO-19 have no such behavior with TASQs. All the spectra and binding mechanisms are similar to known mechanisms or computer-aided molecular simulation models, suggesting that the second generation of hydrophilic TASQs can imitate the natural terminal G-tetrad planes of G-quadruplexes. Moreover, this artificial receptor has selectivity over different ligands with an ability to contribute to the screening of small-molecule ligands, as well as the investigations of binding mechanisms of new anticancer ligands. The main works in this thesis are shown as follows: 1. Introduction to DNA duplexes, G-quadruplexes, template-assembled synthetic G-quartets, anticancer drugs (i.e. PIPER, TMPyP4, AZATRUX, BSU-1051, BRACO 19, telomestatin), and characteristic methods. 2. Synthesis of water-soluble template-assembled G-quartets (TASQ 13), PIPER, and AZATRUX. The binding properties of these ligands with TASQ 13 were characterized by spectroscopic methods so as to show the binding abilities and binding modes of different drugs to TASQ 13. 3. Conclusions and future work.