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The Small Organic Molecules Targeted Human Telomeric G-quadruplex DNA: Design, Synthesis and Binding

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Tutor: WeiChunYing
School: Shanxi University
Course: Inorganic Chemistry
Keywords: G- four chain plasmid DNA,CT-DNA,Phenanthroline Derivative,TPY,Anti-tumor,End,Gr
CLC: TQ460.1
Type: Master's thesis
Year:  2011
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DNA is the basic genetic material of living and the basis of gene expression, and its structure is polymorphic. In addition to the classical structure called Watson-Crick duplex DNA, the G-rich single-strand telomere DNA can fold into a four-stranded structure named G-quadruplexes by Hoogsteen hydrogen bond. It has been proven that ligands being able to selectively recognize and stabilize G-quadruplex DNAs can hinder telomere DNA primer recognition by telomerase and effectively inhibit the telomerase activity. As a result, these ligands inhibit the tumour cell proliferation. So G-quadruplexes constitute a very attractive target for anti-cancer drug design. However there is a large amount of duplex DNA inside the nucleus, in order to improve the effect of anti-cancer and reduce the significant toxicity and the side effects, how to design anti-cancer drugs with high selectivity for G-quadruplex over duplex DNA is the one of the biggest challenges in this field. On the basis of the detail investigation and study for the latest literatures, according to the structural differences between G-quadruplex and duplex DNAs, here we designed and synthesized a series of new small molecule ligand, and their interactions with human telomeric G-quadruplex and CT-DNA were preliminarily studied using spectroscopic method. We screen out three new compounds which can selectively recongnize G-quadruplex over duplex even at levels of 10-fold excess of duplex DNA. The main works in the thesis were shown as follows:1. In this paper we designed and synthesized two 2,2¡¯-bipyridine and four 1,10-phenanthroline new derivatives. The products were characterized by means of IR,1H-NMR, 13C-NMR and ESI-MS spectroscopies.2. The preliminary results of UV and fluorescence spectra indicated that three phenanthroline derivatives may interact with human telomeric G-quadruplex DNA(HTG) by¦Ð-¦Ðstacks of interaction and with the duplex calf thymus DNA(CT-DNA) by the intercalative mode, however the interaction between bipyridine derivative 2 and DNA is relatively weak. The results of CD spectra showed that three phenanthroline derivatives 1-3 have no significant influence on the conformation of HTG in the presence of Na+ medium. But in K+ medium, three compounds can induce the change of G-quadruplex from hybrid to antiparallel structure.3. Thermodynamics results indicate that the interactions between phenanthroline derivatives 1-3 and G-quadruplex were enthalpically driven in the presence of Na+, being that the corresponding AH values were higher than -T¦¤S values. In contrast, owing to the influence of G-quadruplex conformation change, a small positive AH as well as large negative-T¦¤S values found in binding process indicated the entropically favorable binding in K+ medium.4. FRET-melting(Fluorescence Resonance Energy Transfer- melting assay) and competitive FRET-melting assays showed that phenanthroline derivatives 1-3 have much more affinity for telomeric G-quadruplex than bipyridine derivative 2 and can bind G-quadruplex selectively over duplex even at levels of 10 times excess of duplex DNA in the presence of Na+ and K+, and the ability of stabilizing G-quadruplex is greater in K+ buffer than in Na+ buffer. In buffer containing 100 mM KC1, an increase in the melting temperature (ATm) is 15.1,20.2 and 17.9¡æfor G-quadruplex in the presence of 1.0¦ÌM phenanthroline derivatives 1-3.
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