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![Development of Novel Phenanthroline and Thiazole Orange Derived G-Quadruplex Ligands and Telomerase Inhibitors için kapak resmi Development of Novel Phenanthroline and Thiazole Orange Derived G-Quadruplex Ligands and Telomerase Inhibitors için kapak resmi](/client/assets/d79c3e4af2b6d196/ctx/images/no_image.png)
Development of Novel Phenanthroline and Thiazole Orange Derived G-Quadruplex Ligands and Telomerase Inhibitors
Başlık:
Development of Novel Phenanthroline and Thiazole Orange Derived G-Quadruplex Ligands and Telomerase Inhibitors
Yazar:
Wang, Siwen, author.
ISBN:
9780438058903
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (253 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-11(E), Section: B.
Advisors: Liang Xue Committee members: Andreas Franz; Jianhua Ren; Vyacheslav V. Samoshin; Lisa Wrischnik.
Özet:
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.
Notlar:
School code: 0173
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(694579.1) | 694579-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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