Targeting human telomeric DNA with azacyanines

Thesis Type: Postgraduate

Institution Of The Thesis: Middle East Technical University, Faculty of Arts and Sciences, Department of Chemistry, Turkey

Approval Date: 2019

Thesis Language: English

Student: AYÇA DOĞU

Supervisor: Özgül Persil Çetinkol


Small molecules targeting telomeric DNA or its interactions with telomerase have been an active area of cancer research. Within this thesis, a series of five new benzimidazole compounds differing from each other in alkyl chain length and branching in the benzimidazole ring (ethyl, propyl, isopropyl, butyl, and isobutyl) were synthesized and characterized using Nuclear Magnetic Resonance (NMR) spectroscopy, High Resolution Mass spectroscopy and C/H/N elemental analysis. Their interactions with human telomeric DNA (tel24) along with the previously investigated methyl derivative were investigated using UV-VIS, Circular Dichroism, and Fluorescence spectroscopy. All the compounds were found to be binding to tel24 and inducing a weak CD band between 320 nm and 360 nm in 1:1 complexes. Substantial red-shift and hypochromic effect were observed only in the UV-VIS spectrum of Azamethyl and Azabutyl upon binding to tel24. No red shift or hypochromic effect was observed in the UV-VIS spectrum of Azaisopropyl in the presence of tel24. Among the compounds investigated, the butyl derivative was found to be binding to tel24 tighter than the previously investigated methyl derivative. Association constants were found to be 6.61x105 ± (3.74x104 ), 7.84x105 ± (3.44x104 ), and 4.55x105 ± (1.23x104 ) M-1 for Azamethyl, Azabutyl, and Azaisobutyl respectively. Azaisopropyl showed the lowest binding affinity towards tel24. As a result, this study revealed that tel24 was a specific target for Azamethyl, Azabutyl, vi and Azaisobutyl and azacyanines might be plausible drug candidate molecules in targeting G-quadruplexes.