Date of Award

2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Liang Xue

First Committee Member

Andreas Franz

Second Committee Member

Jianhua Ren

Third Committee Member

Vyacheslav V. Samoshin

Abstract

The end of the human chromosome is protected by telomeres which contain a special tandem guanine-rich DNA sequence, 5’-TTAGGG. The length of telomeres is shortened during cell replications, and its length limits the replication capacity of cells. Telomerase is over-expressed in 85–90% of cancer cells, responsible for extending the telomere length in cancer cells. Guanine-rich DNA sequence can self-assemble into unique G-quadruplex structures that interfere with the extension of telomeres by telomerase. Therefore, DNA G-quadruplex has recently received much attention because of its important regulatory functions in telomerase-mediated cancerization. The formation of G-quadruplex requires monovalent cations (Na+ and K+) or small molecules known as G-quadruplex ligands. In the present work, we developed a serial of G-quadruplex ligands by tethering side-chains to two core structures: 1,10-phenanthroline (Phen) and thiazole orange (TO). Biophysical studies including DNA thermal denaturation monitored by fluorescence orcircular dichroism, fluorometric titration, and ESI-MS spectrometry reveal that the binding of the synthesized ligands to G-quadruplex is side-chain dependent. The arylsulfanyl side chains significantly improve the binding affinity and selectivity of 1,10-phenanthroline towards G-quadruplex over duplex DNA. The polyamine side chains are a suitable structural motif for remarkable G-quadruplex binding affinity based on the results from both Phen and TO derivatives. These ligands greatly inhibit the telomerase activity in vitro, determined by a modified telomeric repeat amplification protocol (TRAP) assay. Amongst these promising telomerase inhibitors, a thiazole orange derivative containing a side chain of spermine shows an outstanding telomerase inhibition effect at nanomolar concentrations, which is comparable to the most effective synthetic telomerase inhibitors, BRACO-19.

Pages

251

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