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3,6-Disubstituted 1,2,4-Triazolo[3,4-b]Thiadiazoles with Anticancer Activity Targeting Topoisomerase II Alpha

Authors Sagredou S, Dalezis P, Nikoleousakos N, Nikolaou M, Voura M, Almpanakis K, Panayiotidis MI, Sarli V, Trafalis DT

Received 21 March 2020

Accepted for publication 30 May 2020

Published 28 July 2020 Volume 2020:13 Pages 7369—7386


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Editor who approved publication: Dr Leo Jen-Liang Su

Sofia Sagredou,1 Panagiotis Dalezis,1 Nikolaos Nikoleousakos,1 Michail Nikolaou,1 Maria Voura,2 Konstantinos Almpanakis,2 Mihalis I Panayiotidis,3,4 Vasiliki Sarli,2 Dimitrios T Trafalis1

1Laboratory of Pharmacology, Faculty of Medicine, National and Kapodistrian University of Athens, Athens 11527, Greece; 2Department of Chemistry, Aristotle University of Thessaloniki , Thessaloniki, 54124, Greece; 3Department of Electron Microscopy & Molecular Pathology, The Cyprus Institute of Neurology & Genetics, Nicosia 2371, Cyprus; 4The Cyprus School of Molecular Medicine, Nicosia 1683, Cyprus

Correspondence: Sofia Sagredou; Dimitrios T Trafalis Email;

Background: Topoisomerase IIα (topIIα) maintains the topology of DNA in order to ensure the proper functioning of numerous DNA processes. Inhibition of topIIα leads to the killing of cancer cells thus constituting such inhibitors as useful tools in cancer therapeutics. Triazolo[3,4-b]thiadiazole derivatives are known for their wide range of pharmacological activities while previous studies have documented their in vitro anticancer activity. The purpose of the current study was to investigate if these chemical compounds can act as topIIα inhibitors in cell-free and cell-based systems.
Materials and Methods: The MTT assay was performed in DLD-1, HT-29, and LoVo cancer cells so as to evaluate the antiproliferative activity of KA25, KA26, and KA39 triazolo[3,4-b]thiadiazole derivatives. The KA39 compound was tested as a potential topIIα inhibitor using the plasmid-based topoisomerase II drug screening kit. The inhibitory effect of the three derivatives on topIIα phosphorylation was studied in HT-29 and LoVo cancer cells according to Human Phospho-TOP2A/Topoisomerase II Alpha Cell-Based Phosphorylation ELISA Kit. Moreover, flow cytometry was utilized in order to explore apoptotic induction and cell cycle growth arrest, upon treatment with KA39, in DLD-1 and HT-29 cells, respectively. In silico studies were also carried out for further investigation.
Results: All three triazolo[3,4-b]thiadiazole derivatives showed an in vitro antiproliferative effect with the KA39 compound being the most potent one. Our results indicated that KA39 induced both early and late apoptosis as well as cell cycle growth arrest in S phase. In addition, the compound blocked the relaxation of supercoiled DNA while it also inhibited topIIα phosphorylation (upon treatment; P< 0.001).
Conclusion: Among the three triazolo[3,4-b]thiadiazole derivatives, KA39 was shown to be the most potent anticancer agent and catalytic inhibitor of topIIα phosphorylation as well.

Keywords: triazoles, thiadiazoles, topoisomerase IIα, catalytic cycle, Ser-1106, phosphorylation

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