Abstract
A combination of biochemical, biophysical and biological techniques was used to study calf thymus DNA interaction with newly synthesized 7-MEOTA-tacrine thiourea 12–17 and urea heterodimers 18–22, and to measure interference with type I and II topoisomerases. Their biological profile was also inspected in vitro on the HL-60 cell line using different flow cytometric techniques (cell cycle distribution, detection of mitochondrial membrane potential dissipation, and analysis of metabolic activity/viability). The compounds exhibited a profound inhibitory effect on topoisomerase activity (e.g. compound 22 inhibited type I topoisomerase at 1 µM concentration). The treatment of HL-60 cells with the studied compounds showed inhibition of cell growth especially with hybrids containing thiourea (14–17) and urea moieties (21 and 22). Moreover, treatment of human dermal fibroblasts with the studied compounds did not indicate significant cytotoxicity. The observed results suggest beneficial selectivity of the heterodimers as potential drugs to target cancer cells.
Highlights
Tacrine (9-amino-1,2,3,4-tetrahydroacridine, THA, Figure 1) was first described as an analeptic able to cause rapid arousal of morphinized dogs and cats[1,2]
Effect on topoisomerases lies in introduction DNA of single (Topo I) relaxation activity In this study, we examined the effect of 7-MEOTA-THA thio-/urea derivatives [12,13,14,15,16,17,18,19,20,21,22] on the catalytic activity of Topo I by measuring the Topo I-mediated relaxation of supercoiled plasmid pUC19
We propose that Topo I and II both represent an important target for our studied heterodimers
Summary
Tacrine (9-amino-1,2,3,4-tetrahydroacridine, THA, Figure 1) was first described as an analeptic able to cause rapid arousal of morphinized dogs and cats[1,2]. A potential crosstalk between some types of cancer and modulation of AChE activity has been proposed. The inhibition of AChE affecting cholinergic signaling has been associated with some potential benefits in e.g. cancerous lung tissue[4]. The effect of THA has been well-described in neurological diseases[5]. THA was licensed in USA and Canada as the first symptomatic treatment for cognitive symptoms associated with Alzheimer’s disease (the drug Cognex)[6]. Clinical use of THA was limited due to its side effects, mainly hepatotoxicity and gastrointestinal symptoms[7]. Some researchers associate the THA-associated hepatotoxicity with oxidative bio-activation and the formation of chemically highly reactive metabolites[9]; the cell-killing effect is more probably mediated by membrane fluidity alterations[10,11,12]. Apart from that, mitochondrial dysfunction[13] and necrosis of liver cells[7] emerged as other routes for THA toxicity
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