Synthesis of Telomere-Directed DNA Alkylating Agent: Potential Inhibitor of Telomerase
Date Issued
2010
Date
2010
Author(s)
Hu, Tsung-Hao
Abstract
The reduction of telomeres length during cell division can lead to genomic instability and senescence.1 Telomere repeats are added by telomerase, which is overexpressed in most tumor cells for the unlimited cell proliferation. Of particular interest is that telomeres can fold into G-quartet structure which cannot be elongated by telomerase. Recently, 3,6-Bis(1-methyl-4-vinylpyridinium)carbazole diiodide (BMVC), a G-quartet stabilizer, was reported, showing telomerase inhibition ability along with fluorescence enhancement while intercalating with G-quadruplex.2 Based on the simulation results, BMVC intercalated with G-quartet on the top or bottom of the G-tetrad more likely.3
Consequently, introducing nitrogen mustard as DNA-alkylating agent tethered to BMVC could form covalent linkage with neighboring DNA backbone, rendering it become a stronger G-quartet stabilizer. In this thesis, we designed linkers with three different length, which links BMVC and nitrogen mustard, hoping to covalently linked with neighboring bases while binding with G-quadruplex.
These BMVC derivatives possess high fluorescence quantum yield as well as show strong chemical ligation ability. We analyzed the interactions between BMVC derivatives and G-quadruplex by UV/Vis spectroscopy, fluorescence spectroscopy, circular dichroism, as well as DNA-PAGE studies. On the other hand, we successfully detected and analyzed DNA adducts by mass spectrometry.
Subjects
telomere
G-quadruplex
alkylating agents
telomerase
inhibitor
Type
thesis
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