Show/Hide Menu
Hide/Show Apps
Logout
Türkçe
Türkçe
Search
Search
Login
Login
OpenMETU
OpenMETU
About
About
Open Science Policy
Open Science Policy
Open Access Guideline
Open Access Guideline
Postgraduate Thesis Guideline
Postgraduate Thesis Guideline
Communities & Collections
Communities & Collections
Help
Help
Frequently Asked Questions
Frequently Asked Questions
Guides
Guides
Thesis submission
Thesis submission
MS without thesis term project submission
MS without thesis term project submission
Publication submission with DOI
Publication submission with DOI
Publication submission
Publication submission
Supporting Information
Supporting Information
General Information
General Information
Copyright, Embargo and License
Copyright, Embargo and License
Contact us
Contact us
Insights into the action mechanism of azacyanines: their Topoisomerase IIα inhibition potential and nucleic acid selectivity
Download
index.pdf
Date
2018
Author
Güloğlu, Sercan
Metadata
Show full item record
Item Usage Stats
201
views
90
downloads
Cite This
Topoisomerase II alpha (Topo IIα) is one of the essential enzymes in cell viability. It is required for cell cycle progression due to its role in regulating the topological constraints during DNA replication and transcription. Due to its role, Topo IIα became one of the extensively exploited targets in chemotherapy, and there is an on-going research in design of small molecules targeting topoisomerase’s catalytic activity at different stages using different mechanisms. Within the scope of this thesis first, the effects of five azacyanine derivatives on Topoisomerase IIα enzyme (Topo IIα) at molecular level have been assessed by using an in-vitro Topoisomerase Drug Screening kit. Three of the azacyanines (Azamethyl, Azaethyl and Azaisobutyl) used were benzimidazole derivatives differing from each other in terms of the alkyl chain length on the benzimidazole ring and two of them were benzothiazoles (Aza4 and Aza5). Second, the affinity and selectivity of these compounds towards different nucleic acid sequences and structures have been investigated by using competition dialysis method. Our primary goal was to accentuate azacyanines as probable Topo IIα inhibitors, and provide some mechanistic explanations for their effects. Our results revealed that three of the five azacyanine molecules investigated in here decreases the catalytic activity of Topo IIα. Detailed investigation of the effect of Azamethyl on Topo IIα revealed that the effect on Topo IIα was concentration dependent, such that the higher Azamethyl concentrations led to stronger effect as determined by the intensity of the DNA bands in ethidium bromide (EtBr) stained agarose gels. Moreover, when used at the same concentrations (50.0 µM), Azamethyl showed stronger effect than Etoposide which is a well-known Topo IIα inhibitor being used in chemotherapy. Even better, the efficiency of 50.0 μM Azamethyl was higher than 500.0 μM Etoposide. To shed light onto the mechanism of Topo IIα catalytic activity change, we further investigated the affinity and selectivity of azacyanines towards different nucleic acid sequences and structures via competition dialysis. We included three more azacyanines (Azapropyl, Azabutyl and Azaisopropyl) in our competition dialysis setup to understand the effect of the chain length and branching on the benzimidazole ring in nucleic acid binding affinity and selectivity. Our results revealed that the azacyanines were highly selective towards triple helical nucleic acid structure poly(dA).[poly(dT)]2. More importantly, their affinity and selectivity towards poly(dA).[poly(dT)]2 was decreasing with the increasing linear alkyl chain length, and increasing branching. The order of affinity was Azamethyl > Azaethyl > Azapropyl > Azabutyl > Azaisobutyl > Azaisopropyl. Altogether, the findings presented in here demonstrate the potential of azacyanines to inhibit Topo IIα’s catalytic activity.
Subject Keywords
Azacyanines.
,
Nucleic acids.
,
Chemical inhibitors.
,
DNA topoisomerase II.
URI
http://etd.lib.metu.edu.tr/upload/12622079/index.pdf
https://hdl.handle.net/11511/27286
Collections
Graduate School of Natural and Applied Sciences, Thesis
Suggestions
OpenMETU
Core
Investigation of the therapeutic effect of sodium butyrate in Caco-2 colon cancer cell line by using ATR-FTIR spectroscopy
Çelik, Buket; Bek, Alpan; Özek, Nihal Şimşek; Department of Micro and Nanotechnology (2018)
Sodium butyrate (NaBt), as one of the HDACi, has been demonstrated that it induces apoptosis, cell cycle arrest, the inhibition of angiogenesis, metastasis and gene expression changes. To date, there are several studies perfomed to investigate its therapeutic effect; however, theexact mechanism at molecular level is not clear yet. Therefore, the current thesis was aimed to clarify the action/theurapeutic potential mechanisms of sodium butyrate in Caco2 colon cancer cell line at molecular level using ATR-FTI...
Development of sandwich type nucleic acid array platform for the detection of micrornas in breast cancer
Atılgan, Seren; Öktem, Hüseyin Avni; Department of Biology (2014)
MicroRNAs are small non-coding RNAs that are involved in important regulatory pathways such as differentiation, development, metabolism, cell proliferation, and cell death. Several recent research show that deregulated expression of miRNAs has crucial roles in disease pathologies, mainly in cancer. Therefore, it is likely that the usage of miRNAs as diagnostic and prognostic biomarkers in patients and the development of various techniques for the detection of microRNA in clinical research will become widesp...
Integration of topological measures for eliminating non-specific interactions in protein interaction networks
BAYIR, Murat Ali; GUNEY, Tacettin Dogacan; Can, Tolga (Elsevier BV, 2009-05-28)
High-throughput protein interaction assays aim to provide a comprehensive list of interactions that govern the biological processes in a cell. These large-scale sets of interactions, represented as protein-protein interaction networks, are often analyzed by computational methods for detailed biological interpretation. However, as a result of the tradeoff between speed and accuracy, the interactions reported by high-throughput techniques occasionally include non-specific (i.e., false-positive) interactions. ...
Employing DNA barcoding as taxonomy and conservation tools for fish species censuses at the southeastern Mediterranean, a hot-spot area for biological invasion
Karahan, Arzu; PAZ, Guy; STERN, Nir; Kıdeyş, Ahmet Erkan; Goren, Menachem; RİNKEVİCH, Baruch (2017-04-01)
This study evaluates the utility of DNA barcoding (mitochondrial cytochrome oxidase subunit I; COI) as a biodiversity and conservation applied tool for identifying fish fauna from the southeastern Mediterranean (the continental coast of Israel), a hot-spot area for biological invasion, also with an eye to establish the foundation for follow-up studies that will use environmental DNA (eDNA) tracks of native and invasive species, and for the application of eDNA concepts and methodologies in nature conservatio...
Synthesis of peptide inhibitors for matrix metalloproteinase-2 and angiotensin converting enzyme /
Çiftçi, Burçe; Özçubukçu, Salih; Özen, Can; Department of Biotechnology (2014)
Matrix Metalloproteinases (MMPs) are one of the enzyme families of proteases that have zinc atom in the active site and they are involved in the degradation and regeneration of extracellular matrix. Specifically, they play an important role in tumor formation, tissue invasion, angiogenesis, and tumor metastasis. Matrix metalloprotease-2 (MMP-2) is a member of gelatinase class of MMP family and it has high activity in progression of skin, prostate, bladder, breast, lung, and ovary cancer. To control this inc...
Citation Formats
IEEE
ACM
APA
CHICAGO
MLA
BibTeX
S. Güloğlu, “Insights into the action mechanism of azacyanines: their Topoisomerase IIα inhibition potential and nucleic acid selectivity,” M.S. - Master of Science, Middle East Technical University, 2018.