There has been considerable interest in DNA topoisomerases over the last decade, as they have been shown to be one of the major cellular targets in anticancer drug development. Previously we synthesized some benzothiazole derivatives and corresponding benzothiazolium forms, and tested their DNA inhibitory activity to develop novel antitumor agents. Among the 12 prepared compounds, compound BM3 (3-aminobenzothiazole-3-ium 4-methylbenzene sulfonate) exhibited extreme topoisomerase II inhibitory activity compared with the reference drug etoposide. We also tried to determine the DNA and enzyme binding abilities of BM3 and found that BM3 acted on topoisomerase II first at low doses, while it had also showed DNA minor groove binding properties at higher doses. In this study the interactions between DNA topoisomerase II and the compounds were examined in detail by molecular modelling studies such as molecular docking and pharmacophore analysis performed using Discovery Studio 3.5. As a result, it was found that benzothiazolium compounds exhibited a totally different mechanism than benzothiazoles by binding to the different amino acids at the active site of the protein molecule. 3-Aminobenzothiazoliums are worthy of carrying onto anticancer studies; BM3 especially would be a good anticancer candidate for preclinical studies.
Abstract:Recently, NK1R (Neurokinin-1 receptors) take attention as new and promising target in anticancer drug development area. It has been proved that non-peptide NK1R antagonists L-733,060, aprepitant and L-732,138 inhibited tumor growth in several cancer cell lines. For the development of novel NK1R antagonists as antitumor agents, heterocyclic compounds which were previously synthesized by our team, tested for their cytotoxic activities in several cancer cell lines in this study. Among the tested compounds, a benzothiazole derivative BSN-009 inhibited colon cancer cell lines growth by 57.53% by comparing the activity to the control drug aprepitant. Molecular modeling studies such as molecular docking and pharmacophore generation were performed with known NK1R antagonists and BSN-009 by using Discovery Studio 3.5 in order to explain their binding modes to NK1R. BSN-009 may be a good anticancer drug candidate as a possible NK1R antagonist and is worthy to carry on the anticancer studies.
Background:
Targeting the DNA topoisomerase II enzyme (topo II) is a promising anticancer treatment approach. TopoII controls and modifies the topological states of DNA and plays key roles in DNA replication, transcription
and chromosome segregation. The DNA binding and cleavage domain is one of the active sites of this enzyme. It is
known that topoisomerase inhibitors, also known as topoisomerase poisons, bind to the transient enzyme-DNA complex
and inhibit the religation of DNA, generating single- and double-stranded breaks that harm the integrity of the genome.
This ultimately leads to the accumulation of DNA strand breaks and cell death.
Methods:
Our previously synthesized benzazole derivatives were tested for their eukaryotic DNA topoisomerase II inhibitory activity in a cell free system. Their interactions with the enzyme were studied by carrying out molecular docking
studies using and comparing two different docking programs.
Result:
Docking studies results were clarified binding modes of these compounds to the topoisomerase II enzyme.
Conclusion:
This study also provides guidelines to design novel and more potent antitumor agents functioning as human
topoisomerase II enzyme inhibitors.
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