Synthesis and Evaluation of Antiproliferative Activity, Topoisomerase IIα Inhibition, DNA Binding and Non-Clinical Toxicity of New Acridine-Thiosemicarbazone Derivatives

In this study, we report the synthesis of twenty new acridine-thiosemicarbazone derivatives and their antiproliferative activities. Mechanisms of action such as the inhibition of topoisomerase IIα and the interaction with DNA have been studied for some of the most active derivatives by means of both...

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Main Authors: Gleyton Sousa (Author), Maria C. F. de Almeida (Author), Lucas L. Lócio (Author), Vanda L. dos Santos (Author), Daniel P. Bezerra (Author), Valdenizia R. Silva (Author), Sinara M. V. de Almeida (Author), Alice Simon (Author), Thiago da S. Honório (Author), Lucio M. Cabral (Author), Rosane N. Castro (Author), Ricardo O. de Moura (Author), Arthur E. Kümmerle (Author)
Format: Book
Published: MDPI AG, 2022-09-01T00:00:00Z.
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042 |a dc 
100 1 0 |a Gleyton Sousa  |e author 
700 1 0 |a Maria C. F. de Almeida  |e author 
700 1 0 |a Lucas L. Lócio  |e author 
700 1 0 |a Vanda L. dos Santos  |e author 
700 1 0 |a Daniel P. Bezerra  |e author 
700 1 0 |a Valdenizia R. Silva  |e author 
700 1 0 |a Sinara M. V. de Almeida  |e author 
700 1 0 |a Alice Simon  |e author 
700 1 0 |a Thiago da S. Honório  |e author 
700 1 0 |a Lucio M. Cabral  |e author 
700 1 0 |a Rosane N. Castro  |e author 
700 1 0 |a Ricardo O. de Moura  |e author 
700 1 0 |a Arthur E. Kümmerle  |e author 
245 0 0 |a Synthesis and Evaluation of Antiproliferative Activity, Topoisomerase IIα Inhibition, DNA Binding and Non-Clinical Toxicity of New Acridine-Thiosemicarbazone Derivatives 
260 |b MDPI AG,   |c 2022-09-01T00:00:00Z. 
500 |a 10.3390/ph15091098 
500 |a 1424-8247 
520 |a In this study, we report the synthesis of twenty new acridine-thiosemicarbazone derivatives and their antiproliferative activities. Mechanisms of action such as the inhibition of topoisomerase IIα and the interaction with DNA have been studied for some of the most active derivatives by means of both in silico and in vitro methods, and evaluations of the non-clinical toxicities (in vivo) in mice. In general, the compounds showed greater cytotoxicity against B16-F10 cells, with the highest potency for DL-08 (IC<sub>50</sub> = 14.79 µM). Derivatives DL-01 (77%), DL-07 (74%) and DL-08 (79%) showed interesting inhibition of topoisomerase IIα when compared to amsacrine, at 100 µM. In silico studies proposed the way of bonding of these compounds and a possible stereoelectronic reason for the absence of enzymatic activity for CL-07 and DL-06. Interactions with DNA presented different spectroscopic effects and indicate that the compound CL-07 has higher affinity for DNA (Kb = 4.75 × 10<sup>4</sup> M<sup>−1</sup>; Ksv = 2.6 × 10<sup>3</sup> M<sup>−1</sup>). In addition, compounds selected for non-clinical toxicity testing did not show serious signs of toxicity at the dose of 2000 mg/kg in mice; cytotoxic tests performed on leukemic cells (K-562) and its resistant form (K-562 Lucena 1) identified moderate potency for DL-01 and DL-08, with IC<sub>50</sub> between 11.45 and 17.32 µM. 
546 |a EN 
690 |a acridine-thiosemicarbazone 
690 |a antiproliferative 
690 |a topoisomerase IIα 
690 |a Medicine 
690 |a R 
690 |a Pharmacy and materia medica 
690 |a RS1-441 
655 7 |a article  |2 local 
786 0 |n Pharmaceuticals, Vol 15, Iss 9, p 1098 (2022) 
787 0 |n https://www.mdpi.com/1424-8247/15/9/1098 
787 0 |n https://doaj.org/toc/1424-8247 
856 4 1 |u https://doaj.org/article/b34c6a67d6bd4f02a04b3f2a8b81145f  |z Connect to this object online.