DNA topoisomerase inhibitory activity and 3D-QSAR analysis of benzazoles


DNA topoisomerases (Topo) are enzymes that isomerise the tertiary structure of DNA without changing its primary structure. The high degree of conservation of these enzymes among prokaryotes and eukaryotes indicates an essential role in cell biology. Because its structure is a double helix, DNA is under tortional stress that results in multiplex twisting of the molecule. To be processed for replication or gene expression, the supercoiled DNA must become accessible to nucleic acid polymerases or components of the transcription machinery. This change requires relaxation and untangling of the intertwined DNA strands, which are the typical tasks of Topo (Hande, 2003). In humans, two classes of Topo are well characterized, type I and type II. Topo type II (Topo II) are useful as drug target, since they have an indispensable function in cell biology and they lack biological redundancy. Inhibitors of these enzymes have become central parts of both primary and adjuvant chemotherapy regimens in neoplastic diseases, and they probably will remain so for the foreseeable future. Classical Topo II inhibiting agents such as epipodophyllotoxins or anthracyclines interfere with the breakage-reunion reaction of Topo II by stabilizing this cleavable complex. The stabilization of the cleavable complex and not the inhibition of the Topo II activity is supposed to play the decisive role in the cytotoxic effect of the classical Topo II interacting agents. Accordingly, resistance against classical Topo II-inhibiting agents can result from any process that leads to an altered binding of Topo II to drugs or DNA and a reduced formation of cleavable complexes. Indeed, it was demonstrated that decreased Topo II catalytic activity can mediate drug resistance to cancer cells (Beck et al., 2001). Because of Topo II is the target for some of the most active anticancer drugs such as etoposide, teniposide, and doxorubicin used in the treatment of human malignancies, detailed investigations of biand ter-benzimidazole derivatives revealed that these compounds constitute a new class of Topo I and II inhibitors. Work on such compounds indicates that a fused ring system in the structure is critical for the activity. In the past years, we synthesized several derivatives of benzazoles, such as benzoxazoles, benzimidazoles, benzothiazoles, and oxazolo(4,5-b)pyridines as isosteric fused heterocyclic compounds to investigate their eukaryotic DNA Topo II inhibitory activity (Pinar et al. 2004) and realized their three dimentional quantitative structure activity relationships (3D-QSAR) analysis by using comparative molecular similarity indices analysis (COMSIA) method (Tekiner-Gulbas et al., 2006). A training set of 37 compounds of benzazoles, which are possessing benzoxazole, benzimidazole, benzothiazole, and oxazolo(4,5-b)pyridine fused heterocylic nucleus at their structure, were tested for their eukaryotic DNA Topo II inhibitor activity in cell-free system by using relaxation assay. The relaxation assay utilises supercoiled plasmid as substrate and has been used by many investigators to study the catalytic activity of Topo I and II types. Inhibitory activities were presented as micromolar concentrations of the compounds that cause 50% inhibition per unit of enzyme (IC50), under the assay conditions. From the plots obtained with three different concentrations of the drugs, IC50 values were obtained and the results are the averages of two to three estimations. If no inhibition was obtained at 100 μM, the drug was assumed to have no inhibitory activity on eukaryotic DNA Topo II (Pinar et al., 2004). For the 3D-QSAR studies performed by using CoMSIA methods running the SYBYL program package with

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@inproceedings{AkYalcin2016DNATI, title={DNA topoisomerase inhibitory activity and 3D-QSAR analysis of benzazoles}, author={Esin Akı-Yalcin and Ismail Yalçin}, year={2016} }